scholarly journals GWAS in 446,118 European adults identifies 78 genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

2018 ◽  
Author(s):  
Hassan S Dashti ◽  
Samuel E Jones ◽  
Andrew R Wood ◽  
Jacqueline M Lane ◽  
Vincent T. van Hees ◽  
...  
Keyword(s):  
Sleep Duration ◽  
Brain Regions ◽  
Causal Link ◽  
European Ancestry ◽  
Association Analyses ◽  
Genome Wide ◽  
Synaptic Neurotransmission ◽  
Impact Accelerometer ◽  
The Uk ◽  
Genetic Contributions

AbstractSleep is an essential homeostatically-regulated state of decreased activity and alertness conserved across animal species, and both short and long sleep duration associate with chronic disease and all-cause mortality1,2. Defining genetic contributions to sleep duration could point to regulatory mechanisms and clarify causal disease relationships. Through genome-wide association analyses in 446,118 participants of European ancestry from the UK Biobank, we discover 78 loci for self-reported sleep duration that further impact accelerometer-derived measures of sleep duration, daytime inactivity duration, sleep efficiency and number of sleep bouts in a subgroup (n=85,499) with up to 7-day accelerometry. Associations are enriched for genes expressed in several brain regions, and for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission, catecholamine production, synaptic plasticity, and unsaturated fatty acid metabolism. Genetic correlation analysis indicates shared biological links between sleep duration and psychiatric, cognitive, anthropometric and metabolic traits and Mendelian randomization highlights a causal link of longer sleep with schizophrenia.

scholarly journals Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits

2016 ◽  
Author(s):  
Jacqueline M. Lane ◽  
Jingjing Liang ◽  
Irma Vlasac ◽  
Simon G. Anderson ◽  
David A. Bechtold ◽  
...  
Keyword(s):  
Sleep Duration ◽  
Excessive Daytime Sleepiness ◽  
Daytime Sleepiness ◽  
Sleep Disturbances ◽  
Metabolic Diseases ◽  
Genome Wide Association ◽  
Association Analyses ◽  
Genome Wide ◽  
The Uk ◽  
Insomnia Symptoms

Chronic sleep disturbances, associated with cardio-metabolic diseases, psychiatric disorders and all-cause mortality1,2, affect 25–30% of adults worldwide3. While environmental factors contribute importantly to self-reported habitual sleep duration and disruption, these traits are heritable4–9, and gene identification should improve our understanding of sleep function, mechanisms linking sleep to disease, and development of novel therapies. We report single and multi-trait genome-wide association analyses (GWAS) of self-reported sleep duration, insomnia symptoms including difficulty initiating and/or maintaining sleep, and excessive daytime sleepiness in the UK Biobank (n=112,586), with discovery of loci for insomnia symptoms (near MEIS1, TMEM132E, CYCL1, TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR/OPHN1) and a composite sleep trait (near INADL and HCRTR2), as well as replication of a locus for sleep duration (at PAX-8). Genetic correlation was observed between longer sleep duration and schizophrenia (rG=0.29, p=1.90x10−13) and between increased excessive daytime sleepiness and increased adiposity traits (BMI rG=0.20, p=3.12x10−09; waist circumference rG=0.20, p=2.12x10−07).

scholarly journals Genetic Contributions to Multivariate Data-Driven Brain Networks Constructed via Source-Based Morphometry

2020 ◽  
Vol 30 (9) ◽  
pp. 4899-4913
Author(s):  
Amanda L Rodrigue ◽  
Aaron F Alexander-Bloch ◽  
Emma E M Knowles ◽  
Samuel R Mathias ◽  
Josephine Mollon ◽  
...  
Keyword(s):  
Brain Function ◽  
Complex Traits ◽  
Brain Regions ◽  
Data Driven ◽  
Additional Insight ◽  
Genetic Overlap ◽  
Data Driven Approach ◽  
The Uk ◽  
Genetic Contributions ◽  
Insight Into

Abstract Identifying genetic factors underlying neuroanatomical variation has been difficult. Traditional methods have used brain regions from predetermined parcellation schemes as phenotypes for genetic analyses, although these parcellations often do not reflect brain function and/or do not account for covariance between regions. We proposed that network-based phenotypes derived via source-based morphometry (SBM) may provide additional insight into the genetic architecture of neuroanatomy given its data-driven approach and consideration of covariance between voxels. We found that anatomical SBM networks constructed on ~ 20 000 individuals from the UK Biobank were heritable and shared functionally meaningful genetic overlap with each other. We additionally identified 27 unique genetic loci that contributed to one or more SBM networks. Both GWA and genetic correlation results indicated complex patterns of pleiotropy and polygenicity similar to other complex traits. Lastly, we found genetic overlap between a network related to the default mode and schizophrenia, a disorder commonly associated with neuroanatomic alterations.

scholarly journals Elucidating the genetic architecture underlying IGF1 levels and its impact on genomic instability and cancer risk

2021 ◽  
Vol 6 ◽  
pp. 20
Author(s):  
Stasa Stankovic ◽  
Felix R. Day ◽  
Yajie Zhao ◽  
Claudia Langenberg ◽  
Nicholas J. Wareham ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Genome Wide Association Study ◽  
Genetic Regulation ◽  
Epidemiological Studies ◽  
European Ancestry ◽  
Reverse Causality ◽  
Lung Cancers ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

Background: Insulin-like growth factor-1 (IGF1) has been implicated in mitogenic and anti-apoptotic mechanisms that promote susceptibility to cancer development and growth. Previous epidemiological studies have described phenotypic associations between higher circulating levels of IGF1 in adults with higher risks for breast, prostate, ovarian, colorectal, melanoma and lung cancers. However, such evidence is prone to confounding and reverse causality. Furthermore, it is unclear whether IGF1 promotes only the survival and proliferation of cancerous cells, or also the malignant transformation of healthy cells. Methods: We perform a genome-wide association study in 428,525 white European ancestry individuals in the UK Biobank study (UKBB) and identify 831 independent genetic determinants of circulating IGF1 levels, double the number previously reported. Results: Collectively these signals explain ~7.5% of the variance in circulating IGF1 levels in EPIC-Norfolk, with individuals in the highest 10% of genetic risk exhibiting ~1 SD higher levels than those in the lowest 10%. Using a Mendelian randomization approach, we demonstrate that genetically higher circulating IGF1 levels are associated with greater likelihood of mosaic loss of chromosome Y in leukocytes in men in UKBB (OR per +1 SD = 1.038 (95% CI: 1.010-1.067), P=0.008) and 23andMe, Inc. (P=6.8×10-05), a biomarker of genomic instability involved in early tumorigenesis. Genetically higher IGF1 is also associated with higher risks for colorectal (OR = 1.126 (1.048-1.210), P=1.3×10-03) and breast cancer (OR= 1.075 (1.048-1.103), P=3.9×10-08), with similar effects on estrogen positive (ER+) (OR = 1.069 (1.037-1.102), P=2.3×10-05) and estrogen negative (ER-) (OR = 1.074 (1.025-1.125), P=3.9×10-08) subtypes. Conclusions: These findings give an insight into the genetic regulation of circulating IGF1 levels and support a causal role for IGF1 in early tumorigenesis and risks for breast and colorectal cancers.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

2021 ◽  
Vol 32 (4) ◽  
pp. 805-820
Author(s):  
Miguel Verbitsky ◽  
Priya Krithivasan ◽  
Ekaterina Batourina ◽  
Atlas Khan ◽  
Sarah E. Graham ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Vesicoureteral Reflux ◽  
Copy Number ◽  
Genome Wide Association Study ◽  
Clinical Care ◽  
Copy Number Variant ◽  
European Ancestry ◽  
Genome Wide ◽  
Variant Genotype ◽  
The Uk

BackgroundVesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.MethodsA diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry.ResultsAltogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10−8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41–6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10–9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.ConclusionsThese data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

scholarly journals The transferability of lipid loci across African, Asian and European cohorts

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Karoline Kuchenbaecker ◽  
◽  
Nikita Telkar ◽  
Theresa Reiker ◽  
Robin G. Walters ◽  
...  
Keyword(s):  
Association Studies ◽  
Genetic Risk Score ◽  
Genetic Correlations ◽  
Serum Levels ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Gene Environment ◽  
Genome Wide ◽  
The Uk

Abstract Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23–0.28, p < 1.9 × 10−14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.

scholarly journals Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci

PLoS Genetics ◽  
2016 ◽  
Vol 12 (8) ◽  
pp. e1006125 ◽  
Author(s):  
Samuel E. Jones ◽  
Jessica Tyrrell ◽  
Andrew R. Wood ◽  
Robin N. Beaumont ◽  
Katherine S. Ruth ◽  
...  
Keyword(s):  
Sleep Duration ◽  
Genome Wide Association ◽  
Association Analyses ◽  
Genome Wide

scholarly journals The genetic architecture of sporadic and recurrent miscarriage

2019 ◽  
Author(s):  
Triin Laisk ◽  
Ana Luiza G Soares ◽  
Teresa Ferreira ◽  
Jodie N Painter ◽  
Samantha Laber ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Large Scale ◽  
Recurrent Miscarriage ◽  
Meta Analysis ◽  
Chromosome 9 ◽  
Extravillous Trophoblast ◽  
European Ancestry ◽  
Association Analyses ◽  
Progesterone Production ◽  
Genome Wide

Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%,Pmeta=3.2×-8(CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located nearFGF9involved in pregnancy maintenance3and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%,Pmeta=1.3×-8in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.

scholarly journals HLA-B27 and not variation in MICA is responsible for genotype by sex interaction in risk of Ankylosing Spondylitis

2021 ◽  
Author(s):  
Zhixiu Li ◽  
Allan F McRae ◽  
Geng Wang ◽  
Jonathan J Ellis ◽  
Tony J Kenna ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Complex Traits ◽  
Hla B27 ◽  
Uk Biobank ◽  
Association Analyses ◽  
Genome Wide ◽  
Conditional Association ◽  
A Genome ◽  
Mhc Locus ◽  
The Uk

Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus. The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors' report is unlikely to be a result of variation in MICA, but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.

scholarly journals Genome-wide association analyses in >119,000 individuals identifies thirteen morningness and two sleep duration loci

2016 ◽  
Author(s):  
Samuel E Jones ◽  
Jessica Tyrrell ◽  
Andrew R Wood ◽  
Robin N Beaumont ◽  
Katherine S Ruth ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Circadian Rhythms ◽  
Sleep Duration ◽  
Association Studies ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Association Analyses ◽  
Genome Wide

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but little is known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 White British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness [95%CI 1.15, 1.27], P=3x10-12) and PER2 (1.09 odds of morningness [95%CI 1.06, 1.12], P=4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,823 23andMe participants; thirteen of the chronotype signals remained significant at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. For sleep duration, we replicated one known signal in PAX8 (2.6 [95%CIs 1.9, 3.2] minutes per allele P=5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 [95% CI: 1.3, 2.7] minutes per allele, P=1.2x10-9; and 1.6 [95% CI: 1.1, 2.2] minutes per allele, P=7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG=0.056, P=0.048); undersleeping and BMI (rG=0.147, P=1x10-5) and oversleeping and BMI (rG=0.097, P=0.039), Mendelian Randomisation analyses provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study provides new insights into the biology of sleep and circadian rhythms in humans.

scholarly journals Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

2017 ◽  
Author(s):  
Claudia L Satizabal ◽  
Hieab HH Adams ◽  
Derrek P Hibar ◽  
Charles C White ◽  
Jason L Stein ◽  
...  
Keyword(s):  
Drug Targets ◽  
Brain Structures ◽  
Association Analyses ◽  
Subcortical Brain ◽  
Genome Wide ◽  
Evolutionarily Conserved ◽  
Subcortical Brain Structures ◽  
The Uk ◽  
Potential Drug Targets ◽  
Subcortical Volumes

AbstractSubcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Sign in / Sign up

Export Citation Format

Share Document