| 1. |
- Bergh, Cecilia, 1972-, et al.
(författare)
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Determinants in adolescence of stroke-related hospital stay duration in men : a national cohort study
- 2016
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Ingår i: Stroke. - Philadelphia, USA : Lippincott Williams & Wilkins. - 0039-2499 .- 1524-4628. ; 47:9, s. 2416-2418
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Physical and psychological characteristics in adolescence are associated with subsequent stroke risk. Our aim is to investigate their relevance to length of hospital stay and risk of second stroke.Methods: Swedish men born between 1952 and 1956 (n=237 879) were followed from 1987 to 2010 using information from population-based national registers. Stress resilience, body mass index, cognitive function, physical fitness, and blood pressure were measured at compulsory military conscription examinations in late adolescence. Joint Cox proportional hazards models estimated the associations of these characteristics with long compared with short duration of stroke-related hospital stay and with second stroke compared with first.Results: Some 3000 men were diagnosed with nonfatal stroke between ages 31 and 58 years. Low stress resilience, underweight, and higher systolic blood pressure (per 1-mm Hg increase) during adolescence were associated with longer hospital stay (compared with shorter) in ischemic stroke, with adjusted relative hazard ratios (and 95% confidence intervals) of 1.46 (1.08-1.89), 1.41 (1.04-1.91), and 1.01 (1.00-1.02), respectively. Elevated systolic and diastolic blood pressures during adolescence were associated with longer hospital stay in men with intracerebral hemorrhage: 1.01 (1.00-1.03) and 1.02 (1.00-1.04), respectively. Among both stroke types, obesity in adolescence conferred an increased risk of second stroke: 2.06 (1.21-3.45).Conclusions: Some characteristics relevant to length of stroke-related hospital stay and risk of second stroke are already present in adolescence. Early lifestyle influences are of importance not only to stroke risk by middle age but also to recurrence and use of healthcare resources among stroke survivors.
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| 2. |
- Bergh, Cecilia, 1972-
(författare)
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Life-course influences on occurrence and outcome for stroke and coronary heart disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although typical clinical onset does not occur until adulthood, cardiovascular disease (CVD) may have a long natural history with accumulation of risks beginning in early life and continuing through childhood and into adolescence and adulthood. Therefore, it is important to adopt a life-course approach to explore accumulation of risks, as well as identifying age-defined windows of susceptibility, from early life to disease onset. This thesis examines characteristics in adolescence and adulthood linked with subsequent risk of CVD. One area is concerned with physical and psychological characteristics in adolescence, which reflects inherited and acquired elements from childhood, and their association with occurrence and outcome of subsequent stroke and coronary heart disease many years later. The second area focuses on severe infections and subsequent delayed risk of CVD. Data from several Swedish registers were used to provide information on a general population-based cohort of men. Some 284 198 males, born in Sweden from 1952 to 1956 and included in the Swedish Military Conscription Register, form the basis of the study cohort for this thesis. Our results indicate that characteristics already present in adolescence may have an important role in determining long-term cardiovascular health. Stress resilience in adolescence was associated with an increased risk of stroke and CHD, working in part through other CVD factors, in particular physical fitness. Stress resilience, unhealthy BMI and elevated blood pressure in adolescence were also associated with aspects of stroke severity among survivors of a first stroke. We demonstrated an association for severe infections (hospital admission for sepsis and pneumonia) in adulthood with subsequent delayed risk of CVD, independent of risk factors from adolescence. Persistent systemic inflammatory activity which could follow infection, and that might persist long after infections resolve, represents a possible mechanism. Interventions to protect against CVD should begin by adolescence; and there may be a period of heightened susceptibility in the years following severe infection when additional monitoring and interventions for CVD may be of value.
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| 3. |
- Bergh, Cecilia, 1972-, et al.
(författare)
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Non-psychotic mental disorders in adolescent men and risk of myocardial infarction : A national cohort study
- 2020
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 41:Suppl. 2, s. 2812-2812
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Purpose: Recent studies show that early life stress is associated with later risk of cardiovascular disease (CVD) and stress may also increase the risk of psychiatric disease. We investigated the association between non-psychotic mental disorders in adolescence and subsequent myocardial infarction, and the role of stress resilience and physical fitness in this association.Method: This is a register-based cohort study with 238 013 males born between 1952 and 1956 followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semi-structured interview with a psychologist. Physical fitness was measured at conscription examination with a cycle ergometer test. A total of 34 503 men were diagnosed with a non-psychotic mental disorder at conscription. Using Cox regression, we estimated the association of mental disorders with myocardial infarction after adjustment for other established CVD risk factors in adolescence. Stress resilience and physical fitness were included in the adjusted model in a second set of analyses.Results: A total of 5891 diagnoses of first myocardial infarction were identified. Non-psychotic mental disorders were associated with an increased risk of myocardial infarction, with a hazard ratio (HR) and confidence interval (CI) of 1.51 (1.41–1.62). The association remained statistically significant after adjustment for other important potential confounders in adolescence such as systolic and diastolic blood pressure, body mass index, inflammation, cognitive function, parental socioeconomic index and a summary disease score (HR 1.24 (CI 1.13–1.35)). The association was further explained by stress resilience and lifestyle factors assessed with a cardiovascular fitness test in adolescence, as the association attenuated but remained statistically significant when further adjusting for stress resilience and physical fitness (HR 1.18 (CI 1.08–1.29)).Conclusion: A non-psychotic mental disorder in adolescences may increase the risk of developing myocardial infarction later in life. This association was partly but not completely explained by poorer stress resilience and physical fitness. Effective prevention might focus on behaviour/lifestyle and psychosocial stress in early life.
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| 4. |
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| 5. |
- Bergh, Cecilia, 1972-, et al.
(författare)
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Severe infections and subsequent delayed cardiovascular disease
- 2017
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Ingår i: European Journal of Preventive Cardiology. - : Sage Publications. - 2047-4873 .- 2047-4881. ; 24:18, s. 1958-1966
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe infections in adulthood are associated with subsequent short-term cardiovascular disease. Whether hospital admission for sepsis or pneumonia is associated with persistent increased risk (over a year after infection) is less well established.Design: The design of this study was as a register-based cohort study.Methods: Some 236,739 men born between 1952-1956 were followed from conscription assessments in adolescence to 2010. All-cause cardiovascular disease ( n = 46,754), including coronary heart disease ( n = 10,279) and stroke ( n = 3438), was identified through national registers 1970-2010 (at ages 18-58 years).Results: Sepsis or pneumonia in adulthood (resulting in hospital admission) are associated with increased risk of cardiovascular disease in the years following infection. The risk is highest during the first year after the infection, with an adjusted hazard ratio (and 95% confidence intervals) of 6.33 (5.65-7.09) and a notably increased risk persisted with hazard ratios of 2.47 (2.04-3.00) for the second and 2.12 (1.71-2.62) for the third year after infection. The risk attenuated with time, but remained raised for at least five years after infection; 1.87 (1.47-2.38). The results are adjusted for characteristics in childhood, cardiovascular risk factors and medical history in adolescence. Similar statistically significant associations were found for coronary heart disease and stroke.Conclusions: Raised risks of cardiovascular disease following hospital admission for sepsis or pneumonia were increased for more than five years after the infection, but with the highest magnitude during the first three years following infection, suggesting a period of vulnerability when health professionals and patients should be aware of the heightened risk for cardiovascular disease.
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| 6. |
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| 7. |
- Bergh, Cecilia, 1972-, et al.
(författare)
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Shared unmeasured characteristics among siblings confound the association of Apgar score with stress resilience in adolescence
- 2019
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell Publishing Inc.. - 0803-5253 .- 1651-2227. ; 108:11, s. 2001-2007
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Tidskriftsartikel (refereegranskat)abstract
- AIM: We investigated the association between low Apgar score, other perinatal characteristics and low stress resilience in adolescence. A within-siblings analysis was used to tackle unmeasured shared familial confounding.METHODS: We used a national cohort of 527,763 males born in Sweden between 1973 and 1992 who undertook military conscription assessments at mean age 18 years (17-20). Conscription examinations included a measure of stress resilience. Information on Apgar score and other perinatal characteristics was obtained through linkage with the Medical Birth Register. Analyses were conducted using ordinary least squares and fixed-effects linear regression models adjusted for potential confounding factors.RESULTS: Infants with a prolonged low Apgar score at five minutes had an increased risk of low stress resilience in adolescence compared to those with highest scores at one minute, with an adjusted coefficient and 95% confidence interval of -0.26 (-0.39, -0.13). The associations were no longer statistically significant when using within-siblings models. However, the associations with stress resilience and birthweight remained statistically significant in all analyses.CONCLUSION: The association with low Apgar score seems to be explained by confounding due to shared childhood circumstances among siblings from the same family, while low birthweight is independently associated with low stress resilience.
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| 8. |
- Bergh, Cecilia, 1972-, et al.
(författare)
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Stress resilience and physical fitness in adolescence and risk of coronary heart disease in middle age
- 2015
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Ingår i: Heart. - : BMJ Publishing Group Ltd. - 1355-6037 .- 1468-201X. ; 101:8, s. 623-629
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Psychosocial stress is a suggested risk for coronary heart disease (CHD). The relationship of stress resilience in adolescence with subsequent CHD risk is underinvestigated, so our objective was to assess this and investigate the possible mediating role of physical fitness.METHODS: In this register-based study, 237 980 men born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semistructured interview with a psychologist. Some 10 581 diagnoses of CHD were identified. Cox regression estimated the association of stress resilience with CHD, with adjustment for established cardiovascular risk factors.RESULTS: Low-stress resilience was associated with increased CHD risk. The association remained after adjustment for physical fitness and other potential confounding and mediating factors, with adjusted HRs (and 95% CIs) of 1.17 (1.10 to 1.25), with some evidence of mediation by physical fitness. CHD incidence rates per 1000 person-years (and 95% CIs) for low-stress, medium-stress and high-stress resilience were 2.61 (2.52 to 2.70), 1.97 (1.92 to 2.03) and 1.59 (1.53 to 1.67) respectively. Higher physical fitness was inversely associated with CHD risk; however, this was attenuated by low-stress resilience, shown by interaction testing (p<0.001).CONCLUSIONS: Low-stress resilience in adolescence was associated with increased risk of CHD in middle age and may diminish the benefit of physical fitness. This represents new evidence of the role of stress resilience in determining risk of CHD and its interrelationship with physical fitness.
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| 9. |
- Bergh, Cecilia, 1972-, et al.
(författare)
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Stress resilience in male adolescents and subsequent stroke risk : cohort study
- 2014
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 85:12, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- Objective Exposure to psychosocial stress has been identified as a possible stroke risk, but the role of stress resilience which may be relevant to chronic exposure is uncertain. We investigated the association of stress resilience in adolescence with subsequent stroke risk.Methods Register-based cohort study. Some 237 879 males born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Cox regression estimated the association of stress resilience with stroke, after adjustment for established stroke risk factors.Results Some 3411 diagnoses of first stroke were identified. Lowest stress resilience (21.8%) compared with the highest (23.7%) was associated with increased stroke risk, producing unadjusted HR (with 95% CIs) of 1.54 (1.40 to 1.70). The association attenuated slightly to 1.48 (1.34 to 1.63) after adjustment for markers of socioeconomic circumstances in childhood; and after further adjustment for markers of development and disease in adolescence (blood pressure, cognitive function and pre-existing cardiovascular disease) to 1.30 (1.18 to 1.45). The greatest reduction followed further adjustment for markers of physical fitness (BMI and physical working capacity) in adolescence to 1.16 (1.04 to 1.29). The results were consistent when stroke was subdivided into fatal, ischaemic and haemorrhagic, with higher magnitude associations for fatal rather than non-fatal, and for haemorrhagic rather than ischaemic stroke.Conclusions Stress susceptibility and, therefore, psychosocial stress may be implicated in the aetiology of stroke. This association may be explained, in part, by poorer physical fitness. Effective prevention might focus on behaviour/lifestyle and psychosocial stress.
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| 10. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 11. |
- Fall, Tove, et al.
(författare)
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The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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| 12. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 13. |
- Grundberg, Elin, et al.
(författare)
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Mapping cis- and trans-regulatory effects across multiple tissues in twins.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
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| 14. |
- Hekne, Linnéa, et al.
(författare)
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Early access to physiotherapy for infants with cerebral palsy : A retrospective chart review
- 2021
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:6
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Forskningsöversikt (refereegranskat)abstract
- AimThis study aimed to investigate whether children with cerebral palsy (CP) had equal access to timely physiotherapy. Additionally, to learn more about clinical characteristics of infants with CP, we explored differences in neonatal clinical history and CP profile between children referred by a neonatologist or enrolled in neonatal follow-up and those referred by other healthcare professionals as well as those referred before and after 5 months corrected age.MethodsWe conducted a retrospective chart review study including children born in Uppsala County, Sweden, from 2010 to 2016, who had received a CP diagnosis by July 2019. Entries by doctors and physiotherapists working at Uppsala University Children’s Hospital were reviewed.ResultsThirty-eight children were included (21 girls, 55.3%) in the study. Twenty-two (57.9%) were born at term. Twenty-five children (66%) had their first visit to a physiotherapist before 5 months corrected age, and this included all children (n = 22, 57.9%) referred by a neonatologist or enrolled in neonatal follow-up. The latter group had significantly earlier access to physiotherapy compared to children referred by other healthcare professionals, with a median of 1.9 (min-max: -1-4) and 7.6 (min-max: 1–24) months, respectively (p < 0.0001). Referral source explained unique variance in predicting time of referral to physiotherapist (R2 0.550, B 4.213, p < 0.0001) when controlling for both number of risk factors and severity of motor impairment. However, number of risk factor was vital for early access to physiotherapy for children referred by other health care professionals.Children referred by a neonatologist or enrolled in neonatal follow-up or referred before 5 months corrected age differed on all measured variables concerning neonatal clinical history and CP profile, compared to children referred by other healthcare professionals or after 5 months corrected age. The latter groups had milder forms of CP. In total, twenty-eight children (73.7%) were ambulatory at 2 years of age. Bilateral spastic CP was most common among those referred by a neonatologist or enrolled in neonatal follow-up or referred before 5 months corrected age, while unilateral spastic CP was most common among those referred by other healthcare professionals or after 5 months corrected age.ConclusionInfants with CP have unequal access to timely physiotherapy, and children considered at low risk for CP receive therapy later. Neonatal follow-up of infants considered at high risk for CP that involves an assessment of motor performance using an evidence-based method during the first months of life corrected age seems to be effective in identifying CP early. Conversely, measuring milestone attainment seems to be a less reliable method for early identification. To provide safe and equal care, all professionals performing developmental surveillance should receive proper training and use evidence-based assessment methods. Physiotherapy should be available prior to formal medical diagnosis.
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| 15. |
- Hiyoshi, Ayako, 1972-, et al.
(författare)
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Comorbidity trajectories in working age cancer survivors : A national study of Swedish men
- 2017
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Ingår i: Cancer Epidemiology. - : Elsevier. - 1877-7821 .- 1877-783X. ; 48, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A large proportion of cancer survivors are of working age, and maintaining health is of interest both for their working and private life. However, patterns and determinants of comorbidity over time among adult cancer survivors are incompletely described. We aimed to identify distinct comorbidity trajectories and their potential determinants.METHODS: In a cohort study of Swedish men born between 1952 and 1956, men diagnosed with cancer between 2000 and 2003 (n=878) were matched with cancer-free men (n=4340) and followed over five years after their first year of survival. Comorbid diseases were identified using hospital diagnoses and included in the analysis using group-based trajectory modelling. The association of socioeconomic and developmental characteristics were assessed using multinomial logit models.RESULTS: Four distinct comorbidity trajectories were identified. As many as 84% of cancer survivors remained at very low levels of comorbidity, and the distribution of trajectories was similar among the cancer survivors and the cancer-free men. Increases in comorbidity were seen among those who had comorbid disease at baseline and among those with poor summary disease scores in adolescence. Socioeconomic characteristics and physical, cognitive and psychological function were associated with types of trajectory in unadjusted models but did not retain independent relationships with them after simultaneous adjustment.CONCLUSIONS: Among working-age male cancer survivors, the majority remained free or had very low levels of comorbidity. Those with poorer health in adolescence and pre-existing comorbid diseases at cancer diagnosis may, however, benefit from follow-up to prevent further increases in comorbidity.
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| 16. |
- Johansson, Martin, et al.
(författare)
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Different aspects of visual perception are important for 12-year social functioning depending on gestational age
- 2023
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 112:7, s. 1537-1547
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Tidskriftsartikel (refereegranskat)abstract
- AimPerceptual mechanisms in social functioning might promote interventions. We investigated relations between visual perception and social functioning, in preterm children.MethodsA prospective preterm cohort born in Uppsala County, Sweden, in 2004–2007 and 49 full-term controls were examined at 12 years. Aspects of visual perception, including static shapes, emotions and time to detect biological motion, were related to social functioning and visual acuity.ResultsThe preterm group comprised 25 extremely preterm children, EPT, born below 28 gestational weeks and 53 children born between 28 and 31 weeks. Preterm children had difficulties in perception of static shapes (p = 0.004) and biological motion (p < 0.001), but not in emotion perception, compared to controls. In the EPT children, poorer shape perception and lower scores on emotion perception were associated with more social problems (p = 0.008) and lower visual acuity (p = 0.004). Shape perception explained more variance in social functioning than emotion perception. In controls, fewer social problems were linked to faster biological motion perception (p = 0.04).ConclusionStatic shape and biological motion perception was affected in the preterm groups. Biological motion perception was relevant for social functioning in full-term children. In EPT children, only shape perception was linked to social functioning, suggesting differential visual perception mechanisms for social deficits.
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| 17. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 18. |
- Karimi, Annette, et al.
(författare)
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Brain MRI findings and their association with visual impairment in young adolescents born very preterm
- 2024
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Ingår i: Neuroradiology. - : Springer. - 0028-3940 .- 1432-1920. ; 66:1, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- PurposeVery preterm birth increases risk for neonatal white matter injury, but there is limited data on to what extent this persists into adolescence and how this relates to ophthalmological outcomes. The aim of this study was to assess brain MRI findings in 12-year-old children born very preterm compared to controls and their association with concurrent ophthalmological outcomes.MethodsWe included 47 children born very preterm and 22 full-term controls (gestational age <32 and >37 weeks, respectively). Brain MRI findings were studied in association with concurrent ophthalmological outcomes at 12-year follow-up.ResultsEvans index (0.27 vs 0.25, p<0.001) and a proposed “posterior ventricle index” (0.47 vs 0.45, p=0.018) were increased in children born very preterm. Higher gestational age associated with larger corpus callosum area (β=10.7, 95%CI 0.59–20.8). Focal white matter lesions were observed in 15 (32%) of very preterm children and in 1 (5%) of full-term controls. Increased posterior ventricle index increased risk for visual acuity ≤1.0 (OR=1.07×1011, 95%CI=7.78–1.48×1021) and contrast sensitivity <0.5 (OR=2.6×1027, 95%CI=1.9×108–3.5×1046). Decreased peritrigonal white matter thickness associated with impaired visual acuity (β=0.04, 95%CI 0.002–0.07).ConclusionMore white matter lesions and evidence of lower white matter volume were found in children born very preterm compared with full-term controls at 12-year follow-up. The association between larger posterior ventricle index and reduced visual acuity and contrast sensitivity suggests disturbances of the posterior visual pathway due to diffuse white matter lesions.
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| 19. |
- Kochukhova, Olga, et al.
(författare)
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Antenatal steroids and neurodevelopment in 12‐year‐old children born extremely preterm
- 2022
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 111:2, s. 314-322
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Tidskriftsartikel (refereegranskat)abstract
- AimTo investigate neurodevelopmental outcome in 12-year-old children born very preterm in relation to perinatal, neonatal and socioeconomic variables. To examine whether previously described positive effects of antenatal steroids on cognition persist at 12 years.MethodsProspective cohort, 78 children with gestational ages 22.7–31.9 weeks, born in 2004–2007 and examined at 12 years of age with cognitive, motor and visual motor integration tasks and compared to an age-matched control group (n = 50). Two preterm subgroups were studied: very preterm children (28–31 gestational weeks, n = 53) and extremely preterm children (22–27 gestational weeks, n = 25).ResultsThe preterm children had significantly lower scores on all cognitive, motor and visual motor integration tasks than the controls. Gestational age and maternal education influenced associations differently in the two preterm subgroups. Also, severe retinopathy of prematurity demonstrated strong associations to outcome. In the extremely preterm group, administration of antenatal steroids was associated with better cognition, basic attention, word generation and motor skills.ConclusionAt 12 years of age, very preterm children born in the 2000s still have deficits across several neurodevelopmental domains compared to term-born peers. Administration of antenatal steroids has long-lasting associations to cognition and motor skills in extremely preterm-born children.
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| 20. |
- Laisk, Triin, et al.
(författare)
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The genetic architecture of sporadic and multiple consecutive miscarriage.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P=3.2 × 10-8, odds ratio (OR)=1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF=6.4%, P=1.3 × 10-8, OR=1.7; rs143445068, MAF=0.8%, P=5.2 × 10-9, OR=3.4; rs183453668, MAF=0.5%, P=2.8 × 10-8, OR=3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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| 21. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 22. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 23. |
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| 24. |
- Mahajan, Anubha, et al.
(författare)
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Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 636-646
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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| 25. |
- Montgomery, Cecilia
(författare)
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Early identification of motor problems in very preterm infants : An evaluation of the Structured Observation of Motor Performance in Infants
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infants born very preterm are at risk of adverse neurodevelopment. It is important to identify motor problems early to initiate interventions aiming at ameliorating outcomes. Evaluating motor development in high-risk infants is a complex task. There is a need for assessment methods for early identification of abnormal motor performance. The aim of this thesis was to evalute the Structured Observation of Motor Performance in Infants (SOMP-I) method for early identification of motor problems in very preterm children and to investigate early motor performance in relation to neonatal characteristics, cerebral imaging and later outcome. Level of motor development and quality of motor performance was assessed at 2, 4, 6, and 10 months’ of corrected age. Study I validated the revised SOMP-I, and compared early motor performance in 111 very preterm infants with 72 full-term infants. The preterm infants were more delayed and had more quality deficits than the term infants, and the groups had different motor trajectories. We concluded that convergent validity and discriminant validity of the SOMP-I was supported and facilitated early identification of infants with atypical motor development.Study II investigated SOMP-I results in relation to motor outcome (Bayley-III motor index at 2.5 years) in 98 very preterm children. The 28 children with delayed development had significantly poorer SOMP-I scores in infancy. We concluded that level and quality of motor performance were significant markers of later motor problems and quality became more significant with increasing age. Study III investigated early motor performance (SOMP-I), in relation to neurodevelopment and motor competence at 12 years (Movement ABC-2) in 78 very preterm children. At all assessment ages, there were significant associations between SOMP-I and MABC-2 scores. At 6 and 10 months, SOMP-I level and quality scores separately explained unique variance of the MABC-2 scores at 12 years. Study IV explored the relation between neonatal cerebral MRI (morphology, apparent diffusion coefficient, regional brain volumes) and 4-month motor performance (SOMP-I), in relation to 2-year motor outcome in 66 very preterm infants (11 with motor problems). SOMP-I results correlated with several MRI measures and with motor outcome. The level of motor performance had the highest predictive value for motor outcome. Overall conclusion: The two SOMP-I domains, level and quality, explain unique variances towards later motor outcomes, meaning that the two separate domains give added value to the motor assessment and are useful markers of motor outcome in very preterm infants.
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| 26. |
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| 27. |
- Montgomery, Cecilia, et al.
(författare)
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Predictive value of Bayley-III Motor Index for later motor difficulties in children born extremely preterm
- 2023
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell. - 0803-5253 .- 1651-2227. ; 112:4, s. 742-752
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate the predictive ability of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Motor Index, in children born extremely preterm (<27 gestational weeks) without cerebral palsy.Methods: Children from the EXPRESS study (all extremely preterm births in Sweden, 2004-2007) without neurosensory impairments assessed with Bayley-III at 2.5 years corrected age and Movement Assessment Battery for Children, Second Edition (MABC-2), at 6.5 years comprised the eligible study population (n = 282). Motor difficulty was defined as MABC-2 <= 5th percentile.Results: Motor difficulties were found in 57 of 282 children (20.2%) at 6.5 years. The Bayley-III explained 18.0% of the variance in the MABC-2 (p < 0.001). The area under the receiver operating curve was 0.71 (95% confidence interval 0.64-0.79, p < 0.001). At a Bayley-III cut-off value of 85, sensitivity, specificity and positive and negative predictive values for motor difficulties were 26.3% (15.5-39.7), 92.9% (88.1-95.9), 48.4% (33.0-64.0) and 83.3% (80.9-85.4). Likelihood ratios were inconclusive.Conclusion: The Bayley-III at 2.5 years corrected age was a modest predictor of motor outcome in children born extremely preterm at 6.5 years, and underestimated the rate of motor difficulties. Children require follow-up beyond preschool age.
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| 28. |
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| 29. |
- Montgomery, Cecilia, et al.
(författare)
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Structured Observation of Motor Performance in Infants : Level and quality associated with later motor development
- 2021
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 110:1, s. 307-313
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Tidskriftsartikel (refereegranskat)abstract
- AimThe aim of this study was to investigate the level of motor development and the quality of motor performance during the first 10 months in relation to the Bayley Scales of Infant Development—third edition (Bayley-III) motor index at 2.5 years.MethodsChildren born very preterm from a population-based study (n = 113) were assessed with the Structured Observation of Motor Performance in Infants (SOMP-I) at 2, 4, 6 and 10 months corrected age and the Bayley-III motor index at 2.5 years corrected age (n = 98). Logistic regressions were performed to investigate the independent association of each SOMP-I domain to Bayley-III motor index.ResultsThere were significant associations between the SOMP-I-scores and Bayley-III motor index per every assessment age. At 4 months, both level and quality were independently associated with a later motor outcome, OR for level was 1.26 (95% CI = 1.08-1.50, P = .002) and for quality, 0.75 (95% CI = 0.63-0.90, P = .002). Quality was independently associated with the Bayley-III motor index at 6 and 10 months: OR 0.080 (95% CI = 0.67-0.95 P = .010) and 0.79 (95% CI = 0.64-0.97, P = .026).ConclusionBoth SOMP-I domains, level and quality, are markers to identify motor problems early. Quality became more important with age.
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| 30. |
- Montgomery, Cecilia, et al.
(författare)
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The Structured Observation of Motor Performance in Infants can detect cerebral palsy early in neonatal intensive care recipients
- 2017
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Ingår i: Early Human Development. - : Elsevier BV. - 0378-3782 .- 1872-6232. ; 113, s. 31-39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe detection of motor problems in infancy requires a detailed assessment method that measures both the infants' level of motor development and movement quality.AimTo evaluate the ability of the Structured Observation of Motor Performance in Infants (SOMP-I) to detect cerebral palsy (CP) in neonatal intensive care recipients.Study designProspective cohort study analyzed retrospectively.Subjects212 (girls: 96) neonatal intensive care recipients (mean gestational age 34 weeks, range: 23–43). Twenty infants were diagnosed with CP.Outcome measuresThe infants were assessed using SOMP-I at 2, 4, 6 and 10 months' corrected age. Accuracy measures were calculated for level of motor development, quality of motor performance and a combination of the two to detect CP at single and repeated assessments.ResultsAt 2 months, 17 of 20 infants with CP were detected, giving a sensitivity of 85% (95% CI 62–97%) and a specificity of 48% (95% CI 40–55%), while the negative likelihood ratio was 0.3 (95% CI 0.1–0.9) and the positive likelihood ratio was 1.6 (95% CI 1.3–2.0). At 6 months all infants with CP were detected using SOMP-I, and all infants had repeatedly been assessed outside the cut-offs. Specificity was generally lower for all assessment ages, however, for repeated assessments sensitivity reached 90% (95% CI 68–99%) and specificity 85% (95% CI 79–90%).ConclusionsSOMP-I is sensitive for detecting CP early, but using the chosen cut-off can lead to false positives for CP. Assessing level and quality in combination and at repeated assessments improved predictive ability.
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| 31. |
- Montgomery, Cecilia, et al.
(författare)
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The Structured Observation of Motor Performance in Infants has convergent and discriminant validity in preterm and term infants
- 2017
-
Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 106:5, s. 740-748
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Methods are needed to evaluate the level of early motor development and quality of motor performance in infants. We examined the convergent and discriminant validity of the Structured Observation of Motor Performance in Infants (SOMP-I) for evaluating the level of motor development and quality of motor performance in preterm and term infants.METHODS: A regional cohort of 111 preterm infants with a gestational age of <32 weeks and 72 healthy term born infants were assessed with the SOMP-I, at two, four, six and 10 months of corrected age. Convergent validity was analysed with a mixed model analysis of the motor performance over time. Discriminant validity was analysed with the Mann-Whitney U-test in groups with different neonatal characteristics.RESULTS: Convergent validity was supported, as the level of motor development increased with age and the quality of motor performance improved over time. The method discriminated for both level and quality between the preterm and the term infants. The preterm infants demonstrated different quality deficits regardless of the level of motor development.CONCLUSION: Convergent validity and discriminant validity of the SOMP-I were supported in preterm and term infants and facilitates early identification of infants with atypical motor development.
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| 32. |
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| 33. |
- Montgomery, Scott, 1961-, et al.
(författare)
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Sex of older siblings and cognitive function
- 2017
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Konferensbidrag (refereegranskat)abstract
- Background : Number of older siblings is associated with lower cognitive function, possibly as marker of material disadvantage. Sex differences may signal an influence of inter-sibling interactions.Methods: The study used a national Swedish register-based cohort of men (n=644,603), born between 1970 and 1992 who undertook military conscription assessments in adolescence that included cognitive function measured on a normally-distributed scale of 1-9. Associations with siblings were investigated using linear regression.Results: After adjustment for numbers of younger siblings, year of conscription assessment, age/year of birth, sex, European socioeconomic classification for parents and maternal age at delivery; the regression coefficients (and 95% confidence intervals) for cognitive function are -0.26 (-0.27, -0.25), -0.42 (-0.44, -0.40), and -0.72 (-0.76, -0.67) for one, two and three or more male older siblings, respectively, compared with none; and -0.22 (-0.23, -0.21), -0.39 (-.41, -0.37), -0.62 (-0.67, -0.58) for one two and three or more female older siblings, respectively, compared with none. A larger number of younger siblings is not associated with lower cognitive function in the adjusted model.Conclusions: Family size is associated with cognitive function: older male siblings may have greater implications than females due to their demands on familial resources or through inter-sibling interactions.
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| 34. |
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| 35. |
- Montgomery, Scott, 1961-, et al.
(författare)
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Sex of older siblings and stress resilience
- 2018
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Ingår i: Longitudinal and Life Course Studies. - : Society for Longitudinal and Life Course Studies. - 1757-9597. ; 9:4, s. 447-455
-
Tidskriftsartikel (refereegranskat)abstract
- The aim was to investigate whether older siblings are associated with development of stress resilience in adolescence and if there are differences by sex of siblings. The study used a Swedish register-based cohort of men (n=664 603) born between 1970 and 1992 who undertook military conscription assessments in adolescence that included a measure of stress resilience: associations were assessed using multinomial logistic regression. Adjusted relative risk ratios (95% confidence intervals) for low stress resilience (n=136 746) compared with high (n=142 581) are 1.33 (1.30, 1.35), 1.65 (1.59, 1.71) and 2.36 (2.18, 2.54) for one, two and three or more male older siblings, compared with none. Equivalent values for female older siblings do not have overlapping confidence intervals with males and are 1.19 (1.17, 1.21), 1.46 (1.40, 1.51) and 1.87 (1.73, 2.03). When the individual male and female siblings are compared directly (one male sibling compared with one female sibling, etc.) and after adjustment, including for cognitive function, there is a statistically significant (p<0.005) greater risk for low stress resilience associated with male siblings. Older male siblings may have greater adverse implications for psychological development, perhaps due to greater demands on familial resources or inter-sibling interactions.
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| 36. |
- Morris, Andrew P, et al.
(författare)
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Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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| 37. |
- Nica, Alexandra C, et al.
(författare)
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The architecture of gene regulatory variation across multiple human tissues : the MuTHER study.
- 2011
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
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| 38. |
- Oien, Cecilia Montgomery, et al.
(författare)
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Gender-associated risk factors for cardiac end points and total mortality after renal transplantation : post hoc analysis of the ALERT study
- 2006
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Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 20:3, s. 374-82
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Female gender offers a cardioprotective effect over men in the general population, but is lost in the dialysis population. Whether renal transplantation restores the gender-dependent cardiac protection and whether there is a difference in the impact of risk factors is not known. METHODS: This is a post hoc analysis of pre-defined end points in the placebo arm in the Assessment of Lescol in Renal Transplantation (ALERT) study, a study in renal transplant recipients. Cox regression was performed to estimate the association between different risk factors at baseline and non-fatal myocardial infarction (MI) or cardiac death and total mortality, and specifically assess whether there are gender differences. RESULTS: The placebo arm included 1052 patients (mean age 50.1 +/- 11.1 yr, 65.3% males) with a mean follow-up of 65 months. The incidence of non-fatal MI or cardiac death was 10.9% vs. 7.9% (NS) and total mortality 13.3% vs. 12.8% (NS) in men and women. In multivariate analysis, previous coronary heart disease (CHD), diabetes, treatment for rejection and serum triglycerides were predictive for cardiac events in men, and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio only in women. A slightly different risk-factor pattern appeared for total mortality. Diabetes, ECG abnormalities, plasma triglycerides, serum creatinine, time on dialysis and age predicted total mortality in men, while ECG abnormalities, LDL/HDL ratio and age were predictors in women. CONCLUSION: In this relatively low-risk population of renal transplant recipients, no gender difference in cardiac events or total mortality was observed, suggesting that female gender advantage regarding CHD is not restored following transplantation. The predictive value of risk factors differed in men and women.
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| 39. |
- Oskarsson, Trausti, et al.
(författare)
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Skeletal adverse events in childhood cancer survivors : An Adult Life after Childhood Cancer in Scandinavia cohort study
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:11, s. 1863-1876
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Tidskriftsartikel (refereegranskat)abstract
- The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26 334 1-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.
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| 40. |
- Rahmioglu, Nilufer, et al.
(författare)
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Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:4, s. 1185-1199
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Tidskriftsartikel (refereegranskat)abstract
- Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.
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| 41. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 42. |
- Setänen, Sirkku, et al.
(författare)
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Using different definitions affected the reported prevalence of neurodevelopmental impairment in children born very preterm
- 2021
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 110:3, s. 838-845
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Tidskriftsartikel (refereegranskat)abstract
- AimWe investigated the impact of varying definitions on the prevalence of neurodevelopmental impairment (NDI) in children born very preterm at 6.5 years of age.MethodsCognitive development and neurosensory impairments were assessed in 91 children (40/51 girls/boys) born <32 gestational weeks, in 2004-2007 in Uppsala county, Sweden. The results were compared with data from a reference group of 67 children born full term. The prevalence of NDI in the present cohort was reported according to definitions used by seven contemporary studies of children born very or extremely preterm.ResultsThe prevalence of severe NDI varied from 2% to 23% depending on the definition used. The prevalence of cognitive impairment varied from 2% (−3 SD according to test norms) to 16% (−2 SD according to control group), the prevalence of cerebral palsy from 0% (severe) to 9% (any) and the prevalence of severe visual impairment from 0% (blindness) to 1% (visual acuity < 0.3). There were no children with severe hearing impairment.ConclusionA high variability in definitions affects the reporting of the prevalence of NDI in long-term follow-up studies of very or extremely preterm born children. There is a need for a better consensus to enable comparisons across studies.
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| 43. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 44. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 45. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 46. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 47. |
- Yang, Jian, et al.
(författare)
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FTO genotype is associated with phenotypic variability of body mass index
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
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Tidskriftsartikel (refereegranskat)abstract
- There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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