| 1. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 2. |
- Wain, Louise V., et al.
(författare)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 3. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 4. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 5. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 6. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 7. |
- Kivipelto, Miia, et al.
(författare)
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World-Wide FINGERS Network : A global approach to risk reduction and prevention of dementia
- 2020
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:7, s. 1078-1094
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Tidskriftsartikel (refereegranskat)abstract
- Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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| 8. |
- Tian, Qu, et al.
(författare)
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Association of Dual Decline in Memory and Gait Speed With Risk for Dementia Among Adults Older Than 60 Years A Multicohort Individual-Level Meta-analysis
- 2020
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Question Is a decline in both memory and gait speed with aging associated with a higher risk of dementia than no decline or a decline in memory or gait only in older adults? Findings In this meta-analysis of 6 studies including 8699 participants from the United States and Europe, a decline in both memory and gait was associated with 6.28 times higher risk of developing dementia than no decline. Meaning Older adults without dementia with parallel declines in memory and gait are associated with high risk of developing dementia and may be a group to target for prevention. This meta-analysis assesses whether parallel declines in memory and gait speed among older adults, compared with those who experience no decline or decline in either memory or gait speed only, are associated with risk of developing dementia. Importance Dual decline in both memory and gait speed may characterize a group of older individuals at high risk for future dementia. Objective To assess the risk of dementia in older persons who experience parallel declines in memory and gait speed compared with those who experience no decline or decline in either memory or gait speed only. Design, Setting, and Participants A multicohort meta-analysis was performed of 6 prospective cohort studies conducted between 1997 and 2018 in the United States and Europe. Participants were 60 years or older, had an initial gait speed of more than 0.6 m/s (ie, free of overt dismobility), with repeated measures of memory and gait speed before dementia diagnosis during a mean follow-up of 6.6 to 14.5 years. Within each study, participants were divided into 4 groups: memory decline only, gait speed decline only, dual decline, or no decline (hereafter referred to as usual agers). Gait decline was defined as a loss of 0.05 m/s or more per year; memory decline was defined as being in the cohort-specific lowest tertile of annualized change. Main Outcomes and Measures Risk of incident dementia according to group membership was examined by Cox proportional hazards regression with usual agers as the reference, adjusted for baseline age, sex, race/ethnicity, educational level, study site, and baseline gait speed and memory. Results Across the 6 studies of 8699 participants, mean age ranged between 70 and 74 years and mean gait speed ranged between 1.05 and 1.26 m/s. Incident dementia ranged from 5 to 21 per 1000 person-years. Compared with usual agers, participants with only memory decline had 2.2 to 4.6 times higher risk for developing dementia (pooled hazard ratio, 3.45 [95% CI, 2.45-4.86]). Those with only gait decline had 2.1 to 3.6 times higher risk (pooled hazard ratio, 2.24 [95% CI, 1.62-3.09]). Those with dual decline had 5.2 to 11.7 times the risk (pooled hazard ratio, 6.28 [95% CI, 4.56-8.64]). Conclusions and Relevance In this study, dual decline of memory and gait speed was associated with increased risk of developing dementia among older individuals, which might be a potentially valuable group for preventive or therapeutic interventions. Why dual decline is associated with an elevated risk of dementia and whether these individuals progress to dementia through specific mechanisms should be investigated by future studies.
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| 9. |
- Han, Xiaolei, et al.
(författare)
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Accelerometer-assessed sedentary behaviour among Chinese rural older adults : Patterns and associations with physical function
- 2022
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Ingår i: Journal of Sports Sciences. - : Informa UK Limited. - 0264-0414 .- 1466-447X. ; 40:17, s. 1940-1949
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Tidskriftsartikel (refereegranskat)abstract
- Sedentary behaviour is associated with a range of adverse health conditions. Population-based studies have rarely examined the distribution and associated factors of accelerometer-measured sedentary behaviour patterns in rural-dwelling older adults. This population-based study included 2096 rural-dwelling older adults (age ≥60 years; 59.0% women) derived from baseline participants of the MIND-China Study. Total sedentary time and patterns (e.g., uninterrupted bouts and breaks) were derived from the hip-worn accelerometers for 7 days. Physical function was assessed using the Short Physical Performance Battery test. Data were analysed using general linear models. Overall, participants spent 58.8% of daily waking time in sedentary behaviour, with nearly half of sedentary time being accumulated through sedentary bouts of 30+ minutes. Men spent more total and accumulated sedentary time than women in each sedentary bout duration, while women had more daily 1+ minute sedentary bouts than men (all P < 0.001). Controlling for moderate-to-vigorous physical activity and other confounders, more prolonged sedentary time and fewer breaks were significantly associated with poor physical function, balance, lower limb strength, and walking speed (all P < 0.001). In older adults living in rural communities, prolonged sedentary behaviour and less frequent breaks are associated with poor physical function.
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| 10. |
- Han, Xiaolei, et al.
(författare)
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Accelerometer-measured sedentary behavior patterns, brain structure, and cognitive function in dementia-free older adults : a population-based study
- 2023
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 96:2, s. 657-668
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sedentary behavior is associated with cognitive impairment, but the neuropathological mechanisms underlying their associations are poorly understood.Objective: To investigate the associations of accelerometer-measured sedentary behavior patterns with brain structure and cognition, and further to explore the potential mechanisms.Methods: This community-based study included 2,019 older adults (age≥60 years, 59% women) without dementia derived from participants in the baseline examination of MIND-China (2018-2020). We assessed sedentary parameters using an accelerometer and cognitive function using a neuropsychological test battery. Structural brain markers were assessed on the structural brain MRI scans in a subsample (n = 1,009). Data were analyzed using the general linear, isotemporal substitution, and mediation models.Results: In the total sample (n = 2,019), adjusting for multiple covariates and moderate-to-vigorous-intensity physical activity, longer mean sedentary bout duration was linearly related with lower z-scores of global cognition, verbal fluency, and memory (ptrend < 0.05), whereas greater total sedentary time was linearly associated with lower z-scores of global cognition, verbal fluency, and memory only among individuals with long sedentary time (>10 h/day) (ptrend < 0.05); Breaking up sedentary time with same amount of light-intensity physical activity was significantly associated with higher verbal fluency and memory z-scores (p < 0.05). In the MRI subsample (n = 1,009), separately entering structural brain MRI markers into the mediation models substantially attenuated the associations of mean sedentary bout duration with global cognition, verbal fluency, and memory z-scores.Conclusion: Prolonged uninterrupted sedentary time is associated with poor global cognition, memory, and verbal fluency among rural older adults, and structural brain markers could partially mediate the association.
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