| 1. |
- Weiner, D. J., et al.
(författare)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 2. |
- Anney, R. J. L., et al.
(författare)
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Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
- 2017
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Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) < 1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P= 9 x10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental- related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
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| 5. |
- Cesta, C. E., et al.
(författare)
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Depression, anxiety, and antidepressant treatment in women: association with in vitro fertilization outcome
- 2016
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 105:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate associations between depression, anxiety, and antidepressants before in vitro fertilization (1VF) and IVF cycle outcomes, including pregnancy, live birth, and miscarriage. Patient(s): Nulliparous women undergoing their first 1VF cycle recorded in the Swedish Quality Register of Assisted Reproduction, January 2007 to December 2012 (n = 23,557). Main Outcome Measure(s): Associations between diagnoses of depression/anxiety, antidepressants, and IVF cycle outcome evaluated using logistic regression to produce adjusted odds ratios (AOR) and 950/o confidence intervals (CI). Result(s): In total, 4.40/o of women had been diagnosed with depression/anxiety and/or dispensed antidepressants before their IVF first cycle. The odds for pregnancy and live birth were decreased (n = 1,044; AOR = 0.86; 950/0 CI, 0.75-0.98; and AOR = 0.83; 950/o CI, 0.720.96, respectively). For women with a prescription for a selective serotonin reuptake inhibitor (SSRI) only (n = 829), no statistically significant associations were found. Women with non-SSRI antidepressants (n = 52) were at reduced odds of pregnancy (AOR = 0.41; 950/0 CI, 0.21-0.80) and live birth (AOR = 0.27; 950/o CI, 0.11-0.68). Women with a depression/anxiety diagnosis with no antidepressant (n = 164) also had reduced odds of pregnancy (AOR = 0.58; 950/0 CI, 0.41-0.82) and live birth (AOR = 0.60; 95% CI, 0.41-0.89). Among the women who became pregnant (39.70/0, there were no statistically significant associations between exposure and miscarriage except for the women taking non-SSRI antidepressants (AOR = 3.56; 950/o CI, 1.06-11.9). Conclusion(s): A diagnosis of depression/anxiety and/or treatment with antidepressants before IVF was associated with slightly reduced odds of pregnancy and live birth. Women with the presence of depression/anxiety without antidepressants had a more pronounced reduction in odds, implying that the underlying disorder is important for the observed association.
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| 8. |
- Whiffin, N, et al.
(författare)
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The effect of LRRK2 loss-of-function variants in humans
- 2020
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
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Tidskriftsartikel (refereegranskat)abstract
- Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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| 15. |
- D'Onofrio, Brian M., et al.
(författare)
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Familial confounding of the association between maternal smoking during pregnancy and offspring substance use and problems
- 2012
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Ingår i: Archives of General Psychiatry. - Chicago, USA : American Medical Association. - 0003-990X .- 1538-3636. ; 69:11, s. 1140-1150
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Tidskriftsartikel (refereegranskat)abstract
- Context: Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy (SDP) causes increased risk of substance use/problems in offspring.Objective: To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design.Design: We used 2 separate samples from the United States and Sweden. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding.Setting: Offspring of a representative sample of women in the United States (sample 1) and the total Swedish population born during the period from January 1, 1983, to December 31, 1995 (sample 2).Patients or Other Participants: Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n = 6904) and all offspring born in Sweden during the 13-year period (n = 1,187,360).Main Outcome Measures: Self-reported adolescent alcohol, cigarette, and marijuana use and early onset (before 14 years of age) of each substance (sample 1) and substance-related convictions and hospitalizations for an alcohol- or other drug-related problem (sample 2).Results: The same pattern emerged for each index of substance use/problems across the 2 samples. At the population level, maternal SDP predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (hazard ratio [HR](moderate), 1.32 [95% CI, 1.22-1.43]; HR(high), 1.33 [1.17-1.53]) to a narcotics-related conviction (HR(moderate), 2.23 [2.14-2.31]; HR(high), 2.97 [2.86-3.09]). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant.Cocnlusions: The association between maternal SDP and offspring substance use/problems is likely due to familial background factors, not a causal influence, because siblings have similar rates of substance use and problems regardless of their specific exposure to SDP.
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| 18. |
- Lundberg, F. E., et al.
(författare)
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Ovarian stimulation and risk of breast cancer in Swedish women
- 2017
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 108:1, s. 137-144
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate whether ovarian stimulation for treating infertility is associated with the risk of breast cancer. Patient(s): In a cohort of 1,340,211 women who gave birth 1982-2012, we investigated the relationship between assisted reproductive technology (ART) and incidence of breast cancer. Associations between any ovarian stimulation since 2005 and breast cancer incidence were studied in a separate cohort of 1,877,140 women born 1960-92. Both cohorts were followed through 2012. Main Outcome Measure(s): Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer. Result(s): There was no increased risk of breast cancer in women who gave birth after ART compared with women who gave birth after spontaneous conception (adjusted HR, 0.84; 95% CI, 0.74-0.95). The incidence of breast cancer was not increased among women who received controlled ovarian stimulation or among women who received other hormonal fertility treatments since 2005, regardless of live birth (adjusted HR, 0.86; 95% CI, 0.69-1.07; and adjusted HR, 0.79; 95% CI, 0.60-1.05, respectively). Conclusion(s): No increased incidence of breast cancer was found among women who had gone through ovarian stimulations, including ART. These results are consistent with other studies and reassuring given the widespread and increasing use of ART. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine.
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| 24. |
- Altman, D., et al.
(författare)
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Somatic Comorbidity in Women with Overactive Bladder Syndrome
- 2016
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 196:2, s. 473-477
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We explore the influence of co-occurring somatic illnesses on prevalent overactive bladder in women of premenopausal age. Materials and Methods: Data for the present study were derived from a nationwide survey on complex diseases among all twins in the Swedish Twin Registry born 1959 to 1985. The present study was limited to female twins participating in the survey (12,850). Generalized estimating equations were used to estimate odds ratios with 95% CIs. Environmental and genetic influences were assessed in co-twin control analysis. Results: Generalized estimating equations analysis showed a significant association between overactive bladder and migraine (OR 1.34, 95% CI 1.15-1.57), fibromyalgia (1.83, 1.54-2.18), chronic fatigue (1.81, 1.49-2.19) and eating disorders (1.56, 1.24-1.96). There was also a significant association with allergic disorders including asthma (1.24, 1.01-1.52) and eczema (1.22, 1.04-1.43). Among reproductive disorders, urinary tract infections (1.60, 1.40-1.84), dysmenorrhea (1.53, 1.33-1.76) and pelvic pain (1.60, 1.31-1.94) showed the strongest association with overactive bladder. Results from co-twin control analysis indicated that the significant associations observed in generalized estimating equations analysis were influenced by environmental and genetic factors without a common pathway model. Conclusions: Our results suggest a multifactorial and complex pathogenesis of overactive bladder in which associations between various somatic illnesses and overactive bladder may be affected by environmental and genetic factors.
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| 28. |
- Cesta, Carolyn E., et al.
(författare)
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A prospective investigation of perceived stress, infertility-related stress, and cortisol levels in women undergoing in vitro fertilization : influence on embryo quality and clinical pregnancy rate
- 2018
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : WILEY. - 0001-6349 .- 1600-0412. ; 97:3, s. 258-268
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionWomen undergoing fertility treatment experience high levels of stress. However, it remains uncertain if and how stress influences in vitro fertilization (IVF) cycle outcome. This study aimed to investigate whether self-reported perceived and infertility-related stress and cortisol levels were associated with IVF cycle outcomes.Material and methodsA prospective cohort of 485 women receiving fertility treatment was recruited from September 2011 to December 2013 and followed until December 2014. Data were collected by online questionnaire prior to IVF start and from clinical charts. Salivary cortisol levels were measured. Associations between stress and cycle outcomes (clinical pregnancy and indicators of oocyte and embryo quality) were measured by logistic or linear regression, adjusted for age, body mass index, education, smoking, alcohol and caffeine consumption, shiftwork and night work. ResultsUltrasound verified pregnancy rate was 26.6% overall per cycle started and 32.9% per embryo transfer. Stress measures were not associated with clinical pregnancy: when compared with the lowest categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest categories of the perceived stress score was 1.04 (95% CI 0.58-1.87), infertility-related stress score was OR = 1.18 (95% CI 0.56-2.47), morning and evening cortisol was OR = 1.18 (95% CI 0.60-2.29) and OR = 0.66 (95% CI 0.34-1.30), respectively.ConclusionsPerceived stress, infertility-related stress, and cortisol levels were not associated with IVF cycle outcomes. These findings are potentially reassuring to women undergoing fertility treatment with concerns about the influence of stress on their treatment outcome.
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| 33. |
- Dagla, C, et al.
(författare)
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The Effect of Antenatal Education on Expectant Fathers' Attitudes toward Breastfeeding and Attachment to the Fetus
- 2023
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Ingår i: Nursing reports (Pavia, Italy). - : MDPI AG. - 2039-4403. ; 13:1, s. 243-254
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study explores the effect of antenatal education on fathers’ attitudes toward: (i) breastfeeding and (ii) attachment to the fetus. A secondary aim is to explore the relationship of fathers’ demographic and the psycho-emotional characteristics that come with breastfeeding and attachment. Methods: This is a longitudinal study involving a group of 216 Greek expectant fathers who participated with their partners in an antenatal educational program performed by midwives in Athens, Greece (September 2020–November 2021). The Iowa Infant Feeding Attitudes Scale (IIFAS) and Paternal Antenatal Attachment Scale (PAAS) were administered at two time points: (a) 24th–28th gestation week and (b) 34th–38th gestation week. The T-test and Univariate Analyses of Variance (ANOVA) were performed. Results: The expectant fathers’ scores show that breastfeeding intention/exclusivity and prenatal attachment to the fetus were higher after their participation in the antenatal education program, but the difference was not statistically insignificant. Expectant fathers with a cohabitation agreement (p = 0.026), who felt very much supported by their partners (p = 0.001) and had no relationship difficulties with their partners (p < 0.001), as well as those who reported being very happy during pregnancy (p < 0.001), showed greater paternal antenatal attachment to the fetus. Conclusions: Although the difference was statistically insignificant, antenatal education appears to have an impact on paternal breastfeeding attitudes and antenatal attachment to the fetus. Additionally, several paternal characteristics were associated with greater antenatal attachment. Future research should be directed toward the investigation of additional factors that impact antenatal–paternal attachment and breastfeeding attitudes so that effective education programs can be designed.
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| 37. |
- Hoffstedt, J, et al.
(författare)
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A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function
- 2001
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 50:10, s. 2410-2413
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary factors may be involved in the pathogenesis of type 2 diabetes. A polymorphism in the hormone-sensitive lipase (HSL) gene (HSLi6) is associated with obesity and diabetes, although it is unknown whether the polymorphism is functional and thereby influences lipolysis. We genotyped 355 apparently healthy nonobese male and female subjects for the HSLi6 polymorphism. Allele 5 was found to be the most common allele (allele frequency 0.57). In 117 of the subjects, we measured abdominal subcutaneous fat cell lipolysis induced by drugs acting at various steps in the lipolytic cascade. The lipolysis rate induced by norepinephrine isoprenaline (acting on β-adrenoceptors), forskolin (acting on adenylyl cyclase), and dibutyryl cyclic AMP (acting on HSL) were all decreased by ∼50% in allele 5 homozygotes, as compared with noncarriers. Heterozygotes showed an intermediate lipolytic rate. The difference in lipolysis rate between genotypes was more pronounced in men than in women. We conclude that allele 5 of the HSLi6 polymorphism is associated with a marked decrease in the lipolytic rate of abdominal fat cells. This may in turn contribute to the development of obesity.
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| 40. |
- Iliadou, A, et al.
(författare)
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Heritabilities of lipids in young European American and African American twins
- 2005
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Ingår i: Twin research and human genetics : the official journal of the International Society for Twin Studies. - : Cambridge University Press (CUP). - 1832-4274. ; 8:5, s. 492-498
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Tidskriftsartikel (refereegranskat)abstract
- Twin studies of lipids have almost exclusively involved Caucasians. People of African descent are known to show a healthier lipid profile, but relatively little is known about ethnic differences in genetic and environmental influences on lipids. One hundred and six African American (AA) and 106 European American (EA) twins (30 singletons and 91 complete pairs: 49 monozygotic, 21 dizygotic and 21 opposite-sex) from the south-eastern United States were studied (mean age 17.9 ± 3.2 years; 79% fasting). Lipids were assayed with the Cholestech LDX system. Analyses were adjusted for fasting status. Generalized estimating equations were used to test for the effects of sex and ethnicity on means, controlling for the dependence within twin pairs. Structural equation modeling was used to estimate genetic and environmental effects on each lipid variable. Females showed higher high-density lipoprotein (HDL) values than males (p< .001) and AAs showed higher HDL values than EAs (p< .001). EA males had higher triglyceride values than other groups (p= .02). All parameter estimates could be set equal across sex. Parameter estimates for total cholesterol, triglycerides and HDL could be set equal across ethnicity. The best fitting model for low- density lipoprotein (LDL) showed higher heritability in AAs (.92) than EAs (.69). Heritabilities ranged from 69% to 92%, with remaining variation explained by nonshared environmental effects. Adjustment for body mass index had virtually no effect on the heritability estimates. In this first twin study on lipids to include AAs, no ethnic differences in heritability were found except for LDL, where AAs exhibited higher estimates.
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| 41. |
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| 43. |
- Iliadou, Anastasia N., et al.
(författare)
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The Uppsala-Stockholm Assisted Reproductive Techniques (UppStART) study
- 2019
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Ingår i: BMJ Open. - : BMJ PUBLISHING GROUP. - 2044-6055. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The Uppsala-Stockholm Assisted Reproductive Techniques (UppStART) study is a prospectively recruited sample of couples undergoing assisted reproduction in Stockholm and Uppsala county in Sweden. The study was initiated to (1) investigate possible changes in the epigenetic profile of infants inferred through the ART procedures and their consequence and (2) to assess the impact of lifestyle and health exposures on treatment outcome.Participants: Recruitment took place between September 2011 and December 2013, and in vitro fertilisation (IVF) cycles initiated and pregnancies conceived during this time were followed until December 2014. The cohort includes 971 participants (n= 514 women; n= 457 men), and 129 pregnancies were achieved from the first IVF cycle included in the study.Findings to date: Self-reported demographic, health and lifestyle data were collected from a baseline questionnaire, and to assess changes to lifestyle, a follow-up questionnaire was issued at the time of oocyte retrieval, and at subsequent IVF cycles. Questionnaire data were linked to data extracted from medical records. Biological samples were collected at baseline: blood for extraction of serum, plasma and DNA, morning and evening saliva samples for cortisol measurement and at delivery including samples of maternal blood, placenta and amniotic fluid, and cord blood for epigenetic analysis.Future plans: Through the unique identification number assigned to each Swedish citizen at birth or immigration, UppStART study participants will be linked to the Swedish population-based national and quality registers to provide data from prenatal, obstetrical, neonatal and infant care, and subsequent updates will provide data on childhood health and educational outcomes. Collaboration and use of UppStART data is encouraged, and more information about access can be found at www.ki.se/meb/uppstart
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| 47. |
- Iliadou, A., et al.
(författare)
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Risk of urinary incontinence symptoms in oral contraceptive users: a national cohort study from the Swedish Twin Register
- 2009
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Ingår i: Fertil Steril. ; 92:2, s. 428-33
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the impact of oral contraceptives on lower urinary tract dysfunction in premenopausal women. DESIGN: Nationwide cohort study. SETTING: National registry. PATIENT(S): A total of 10,791 women (born 1959-1985) from the population- based Swedish Twin Registry who participated in a web-based survey of common diseases. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Symptoms of urinary incontinence. RESULT(S): For users of oral contraception there was a significantly reduced risk for symptoms of stress urinary incontinence, mixed urinary incontinence, and urgency urinary incontinence. The reduction remained significant when adjusting for age, body mass index, and pregnancy history. A reduced prevalence of symptoms of overactive bladder in oral contraceptive users was also observed although the association was nonsignificant. There were no significant associations between lower urinary tract symptoms and women using a levonorgestrel-releasing intrauterine device compared with noncontraceptive users, with the exception of nocturia. CONCLUSION(S): Oral contraceptive use reduces the overall risk for symptoms of urinary incontinence.
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