ABSTRACT
Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
Subject(s)
Functional Laterality/genetics , Genetic Variation/genetics , Adult , Aged , Female , Gene Frequency/genetics , Genetic Loci/genetics , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Quantitative Trait, Heritable , Sex FactorsABSTRACT
Modeling how individuals evolve over time is a fundamental problem in the natural and social sciences. However, existing datasets are often cross-sectional with each individual observed only once, making it impossible to apply traditional time-series methods. Motivated by the study of human aging, we present an interpretable latent-variable model that learns temporal dynamics from cross-sectional data. Our model represents each individual's features over time as a nonlinear function of a low-dimensional, linearly-evolving latent state. We prove that when this nonlinear function is constrained to be order-isomorphic, the model family is identifiable solely from cross-sectional data provided the distribution of time-independent variation is known. On the UK Biobank human health dataset, our model reconstructs the observed data while learning interpretable rates of aging associated with diseases, mortality, and aging risk factors.
ABSTRACT
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Brain/physiology , Child , Child, Preschool , Cohort Studies , Female , Gene Expression Regulation/genetics , Genome-Wide Association Study/methods , Humans , Male , RiskABSTRACT
Through a targeted recruitment 23andMe has collected DNA and patient-reported symptoms from more than 10,000 subjects reporting a physician-verified diagnosis of PD. This study evaluated the potential of self-report, web-based questionnaires to rapidly assess disease natural history and symptomology in genetically-defined PD populations. While average age-at-diagnosis was significantly lower in GBA mutation carriers compared to idiopathic PD, or iPD (idiopathic PD, defined as no GBA mutations and no LRRK2 G2019S mutation), there were no significant differences in symptoms. Conversely, LRRK2 G2019S carrier status significantly associated with reporting of milder daily symptoms of lightheadedness and several differences were observed at a false discovery rate < 0.1, including increased reporting of changes in walking as an initial symptom of disease, decreased reporting of lightheadedness upon standing, and milder symptoms related to daily functioning. The subclinical differences in symptoms reported by LRRK2 G2019S carriers suggest differences in underlying pathophysiology and/or disease progression in LRRK2 carriers compared to iPD. Importantly, we confirm previous findings in PD genetic subsets where disease characteristics were ascertained through clinical exam. Overall, these data support the effective use of self-report and genetic data to rapidly analyze information from a large disease population or difficult to identify genetic subgroups.
Subject(s)
Glucosylceramidase/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mutation, Missense , Parkinson Disease , Self Report , Activities of Daily Living , Adult , Female , Humans , Male , Middle Aged , Parkinson Disease/diagnosis , Parkinson Disease/genetics , Parkinson Disease/physiopathology , Surveys and QuestionnairesABSTRACT
Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
Subject(s)
Refractive Errors/genetics , Adult , Asian People/genetics , Blindness/genetics , Blindness/metabolism , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , Humans , Male , Myopia/genetics , Polymorphism, Single Nucleotide , Refractive Errors/metabolism , Retina/metabolism , Retinal Pigment Epithelium/metabolism , Signal Transduction , White People/geneticsABSTRACT
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
Subject(s)
Depressive Disorder, Major/genetics , Multifactorial Inheritance , Case-Control Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , Humans , Male , Phenotype , Polymorphism, Single Nucleotide , Risk Factors , Schizophrenia/geneticsABSTRACT
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. METHODS: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). RESULTS: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15). CONCLUSIONS: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
Subject(s)
Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease/genetics , Sex Characteristics , Attention Deficit Disorder with Hyperactivity/psychology , Case-Control Studies , Female , Gene Frequency , Genome-Wide Association Study , Humans , Logistic Models , Male , Prevalence , Principal Component AnalysisABSTRACT
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.
Subject(s)
HLA Antigens/genetics , Infections/genetics , White People/genetics , Candidiasis, Vulvovaginal/genetics , Case-Control Studies , Chickenpox/genetics , Chronic Disease , Common Cold/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Hepatitis A/genetics , Hepatitis B/genetics , Herpes Labialis/genetics , Herpes Zoster/genetics , Humans , Infectious Mononucleosis/genetics , Male , Measles/genetics , Meningitis, Bacterial/genetics , Middle Ear Ventilation , Mumps/genetics , Otitis Media/genetics , Otitis Media/surgery , Pharyngitis/genetics , Pneumonia/genetics , Rheumatic Fever/genetics , Rubella/genetics , Scarlet Fever/genetics , Sinusitis/genetics , Streptococcal Infections/genetics , Tonsillectomy , Tonsillitis/genetics , Tonsillitis/surgery , Tuberculin Test , Tuberculosis/diagnosis , Tuberculosis/genetics , Urinary Tract Infections/genetics , Warts/geneticsABSTRACT
Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain â¼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10-89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.
Subject(s)
Genetic Loci/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Psoriasis/genetics , White People/genetics , Age of Onset , Gene Regulatory Networks/genetics , Gene Regulatory Networks/immunology , Humans , Interferons/immunology , Interferons/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism , Polymorphism, Single Nucleotide , Protein Interaction Maps/genetics , Protein Interaction Maps/immunology , Psoriasis/immunology , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
Subject(s)
Birth Order , Genome-Wide Association Study , Parity/genetics , Quantitative Trait Loci , Reproduction/genetics , Reproductive Behavior/physiology , Female , Fertility/genetics , Humans , Maternal Age , Phenotype , Polymorphism, Single Nucleotide/genetics , PregnancyABSTRACT
We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.
Subject(s)
Genetic Predisposition to Disease , Germ Cells/metabolism , Hematopoiesis/genetics , Janus Kinase 2/genetics , Mutation/genetics , Myeloproliferative Disorders/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Demography , Female , Genome-Wide Association Study , Humans , Infant , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Reproducibility of Results , Young AdultABSTRACT
Circadian rhythms are a nearly universal feature of living organisms and affect almost every biological process. Our innate preference for mornings or evenings is determined by the phase of our circadian rhythms. We conduct a genome-wide association analysis of self-reported morningness, followed by analyses of biological pathways and related phenotypes. We identify 15 significantly associated loci, including seven near established circadian genes (rs12736689 near RGS16, P=7.0 × 10(-18); rs9479402 near VIP, P=3.9 × 10(-11); rs55694368 near PER2, P=2.6 × 10(-9); rs35833281 near HCRTR2, P=3.7 × 10(-9); rs11545787 near RASD1, P=1.4 × 10(-8); rs11121022 near PER3, P=2.0 × 10(-8); rs9565309 near FBXL3, P=3.5 × 10(-8). Circadian and phototransduction pathways are enriched in our results. Morningness is associated with insomnia and other sleep phenotypes; and is associated with body mass index and depression but we did not find evidence for a causal relationship in our Mendelian randomization analysis. Our findings reinforce current understanding of circadian biology and will guide future studies.
Subject(s)
Circadian Rhythm/genetics , Depression/epidemiology , Sleep Apnea Syndromes/epidemiology , Sleep Initiation and Maintenance Disorders/epidemiology , Adult , Body Mass Index , F-Box Proteins/genetics , Female , Genetic Variation , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Orexin Receptors/genetics , Period Circadian Proteins/genetics , Polymorphism, Single Nucleotide , RGS Proteins/genetics , Vasoactive Intestinal Peptide/genetics , ras Proteins/geneticsABSTRACT
Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea.
Subject(s)
Genome-Wide Association Study , Rosacea/genetics , Adult , Aged , Alleles , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Genotype , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , HLA-DRB1 Chains/genetics , Histocompatibility Antigens Class II/genetics , Humans , Immunohistochemistry , Inflammation/genetics , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide , Quality Control , Rosacea/metabolismABSTRACT
Roughly one in three individuals is highly susceptible to motion sickness and yet the underlying causes of this condition are not well understood. Despite high heritability, no associated genetic factors have been discovered. Here, we conducted the first genome-wide association study on motion sickness in 80 494 individuals from the 23andMe database who were surveyed about car sickness. Thirty-five single-nucleotide polymorphisms (SNPs) were associated with motion sickness at a genome-wide-significant level (P < 5 × 10(-8)). Many of these SNPs are near genes involved in balance, and eye, ear and cranial development (e.g. PVRL3, TSHZ1, MUTED, HOXB3, HOXD3). Other SNPs may affect motion sickness through nearby genes with roles in the nervous system, glucose homeostasis or hypoxia. We show that several of these SNPs display sex-specific effects, with up to three times stronger effects in women. We searched for comorbid phenotypes with motion sickness, confirming associations with known comorbidities including migraines, postoperative nausea and vomiting (PONV), vertigo and morning sickness and observing new associations with altitude sickness and many gastrointestinal conditions. We also show that two of these related phenotypes (PONV and migraines) share underlying genetic factors with motion sickness. These results point to the importance of the nervous system in motion sickness and suggest a role for glucose levels in motion-induced nausea and vomiting, a finding that may provide insight into other nausea-related phenotypes like PONV. They also highlight personal characteristics (e.g. being a poor sleeper) that correlate with motion sickness, findings that could help identify risk factors or treatments.
Subject(s)
Ear, Inner/embryology , Ear, Inner/physiopathology , Genetic Variation , Glucose/metabolism , Homeostasis , Motion Sickness/etiology , Motion Sickness/physiopathology , Adult , Aged , Alleles , Female , Genetic Association Studies , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide , Sex Factors , Young AdultABSTRACT
OBJECTIVE: The purpose of this study was to conduct a proof-of-concept study to evaluate remote recruitment and assessment of individuals ("virtual research visits") with Parkinson's disease who have pursued direct-to-consumer genetic testing. METHODS: Participants in 23andMe's "Parkinson's Research Community" were contacted by 23andMe. Fifty willing participants living in 23 states underwent a remote, standardized assessment including cognitive and motor tests by a neurologist via video conferencing and then completed a survey. Primary outcomes assessed were (a) proportion of participants who completed the remote assessments; (b) level of agreement (using Cohen's kappa coefficient) of patient-reported data with that of a neurologist; and (c) interest in future virtual research visits. RESULTS: The self-reported diagnosis of Parkinson's disease was confirmed in all cases (k = 1.00). The level of agreement for age of symptom onset (k = 0.97) and family history (k = 0.85) was very good but worse for falling (k = 0.59), tremor (k = 0.56), light-headedness (k = 0.31), and urine control (k = 0.15). Thirty-eight (76%) of the 50 participants completed a post-assessment survey, and 87% of respondents said they would be more or much more willing to participate in future clinical trials if they could do research visits remotely. CONCLUSION: Remote clinical assessments of individuals with known genotypes were conducted nationally and rapidly from a single site, confirmed self-reported diagnosis, and were received favorably. Direct-to-consumer genetic testing and virtual research visits together may enable characterization of genotype and phenotype for geographically diverse populations.
ABSTRACT
Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.
Subject(s)
Genetic Association Studies/methods , Genetic Predisposition to Disease/genetics , Genotyping Techniques/methods , Neurodegenerative Diseases/genetics , Oligonucleotide Array Sequence Analysis/methods , Alleles , Costs and Cost Analysis , Genetic Variation , Genotyping Techniques/economicsABSTRACT
A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ≈ 0.02%), reached genome-wide significance (p < 5 × 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.
Subject(s)
Achievement , Genome-Wide Association Study/methods , Genome-Wide Association Study/statistics & numerical data , Polymorphism, Single Nucleotide/genetics , Educational Status , Genotype , Humans , Massachusetts , Principal Component Analysis , Queensland , Registries , Reproducibility of ResultsABSTRACT
We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
Subject(s)
Genetic Loci , Parkinson Disease/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , Genotype , Humans , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Analysis of genomic segments shared identical-by-descent (IBD) between individuals is fundamental to many genetic applications, from demographic inference to estimating the heritability of diseases, but IBD detection accuracy in nonsimulated data is largely unknown. In principle, it can be evaluated using known pedigrees, as IBD segments are by definition inherited without recombination down a family tree. We extracted 25,432 genotyped European individuals containing 2,952 father-mother-child trios from the 23andMe, Inc. data set. We then used GERMLINE, a widely used IBD detection method, to detect IBD segments within this cohort. Exploiting known familial relationships, we identified a false-positive rate over 67% for 2-4 centiMorgan (cM) segments, in sharp contrast with accuracies reported in simulated data at these sizes. Nearly all false positives arose from the allowance of haplotype switch errors when detecting IBD, a necessity for retrieving long (>6 cM) segments in the presence of imperfect phasing. We introduce HaploScore, a novel, computationally efficient metric that scores IBD segments proportional to the number of switch errors they contain. Applying HaploScore filtering to the IBD data at a precision of 0.8 produced a 13-fold increase in recall when compared with length-based filtering. We replicate the false IBD findings and demonstrate the generalizability of HaploScore to alternative data sources using an independent cohort of 555 European individuals from the 1000 Genomes project. HaploScore can improve the accuracy of segments reported by any IBD detection method, provided that estimates of the genotyping error rate and switch error rate are available.
Subject(s)
Computational Biology/methods , White People/genetics , Computer Simulation , Genetics, Population , Genome, Human , Haplotypes , Humans , PedigreeABSTRACT
BACKGROUND: To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. OBJECTIVE: We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. METHODS: We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). RESULTS: At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)). CONCLUSION: By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.