scholarly journals Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits

2020 ◽  
Author(s):  
Joanna Martin ◽  
Ekaterina A. Khramtsova ◽  
Slavina B. Goleva ◽  
Gabriëlla A M. Blokland ◽  
Michela Traglia ◽  
...  
Keyword(s):  
Sex Differences ◽  
Risk Taking ◽  
Genetic Architecture ◽  
Genetic Correlations ◽  
Related Gene ◽  
Behavioral Traits ◽  
Gene Sets ◽  
Genome Wide ◽  
Z Scores ◽  
Differentiated Effects

AbstractBackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations across these traits, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing genome-wide association study (GWAS) summary statistics for 20 neuropsychiatric and behavioral traits, we tested for differences in SNP-based heritability (h2) and genetic correlation (rg<1) between sexes. For each trait, we computed z-scores from sex-stratified GWAS regression coefficients and identified genes with sex-differentiated effects. We calculated Pearson correlation coefficients between z-scores for each trait pair, to assess whether specific pairs share variants with sex-differentiated effects. Finally, we tested for sex differences in between-trait genetic correlations.ResultsWith current sample sizes (and power), we found no significant, consistent sex differences in SNP-based h2. Between-sex, within-trait genetic correlations were consistently high, although significantly less than 1 for educational attainment and risk-taking behavior. We identified genome-wide significant genes with sex-differentiated effects for eight traits. Several trait pairs shared sex-differentiated effects. The top 0.1% of genes with sex-differentiated effects across traits overlapped with neuron- and synapse-related gene sets. Most between-trait genetic correlation estimates were similar across sex, with several exceptions (e.g. educational attainment & risk-taking behavior).ConclusionsSex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic, requiring large sample sizes. Genes with sex-differentiated effects are enriched for neuron-related gene sets. This work motivates further investigation of genetic, as well as environmental, influences on sex differences.

scholarly journals Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior

2015 ◽  
Vol 5 (4) ◽  
pp. e558-e558 ◽  
Author(s):  
J E Salvatore ◽  
A C Edwards ◽  
J N McClintick ◽  
T B Bigdeli ◽  
A Adkins ◽  
...  
Keyword(s):  
Antisocial Behavior ◽  
Genome Wide Association ◽  
Related Gene ◽  
Immune Related Gene ◽  
Gene Sets ◽  
Genome Wide ◽  
Association Data

scholarly journals Localizing components of shared transethnic genetic architecture of complex traits from GWAS summary data

2019 ◽  
Author(s):  
Huwenbo Shi ◽  
Kathryn S. Burch ◽  
Ruth Johnson ◽  
Malika K. Freund ◽  
Gleb Kichaev ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Empirical Bayes ◽  
Genetic Correlations ◽  
Causal Snps ◽  
European Ancestry ◽  
Risk Scores ◽  
Common Snps ◽  
Genome Wide ◽  
Summary Data

AbstractDespite strong transethnic genetic correlations reported in the literature for many complex traits, the non-transferability of polygenic risk scores across populations suggests the presence of population-specific components of genetic architecture. We propose an approach that models GWAS summary data for one trait in two populations to estimate genome-wide proportions of population-specific/shared causal SNPs. In simulations across various genetic architectures, we show that our approach yields approximately unbiased estimates with in-sample LD and slight upward-bias with out-of-sample LD. We analyze 9 complex traits in individuals of East Asian and European ancestry, restricting to common SNPs (MAF > 5%), and find that most common causal SNPs are shared by both populations. Using the genome-wide estimates as priors in an empirical Bayes framework, we perform fine-mapping and observe that high-posterior SNPs (for both the population-specific and shared causal configurations) have highly correlated effects in East Asians and Europeans. In population-specific GWAS risk regions, we observe a 2.8x enrichment of shared high-posterior SNPs, suggesting that population-specific GWAS risk regions harbor shared causal SNPs that are undetected in the other GWAS due to differences in LD, allele frequencies, and/or sample size. Finally, we report enrichments of shared high-posterior SNPs in 53 tissue-specific functional categories and find evidence that SNP-heritability enrichments are driven largely by many low-effect common SNPs.

scholarly journals A polygenic p factor for major psychiatric disorders

2018 ◽  
Author(s):  
Saskia Selzam ◽  
Jonathan R. I. Coleman ◽  
Avshalom Caspi ◽  
Terrie E. Moffitt ◽  
Robert Plomin
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Architecture ◽  
Genetic Correlations ◽  
Genetic Research ◽  
Strong Support ◽  
Principal Component ◽  
Complex Trait ◽  
Genome Wide ◽  
P Factor ◽  
First Time

AbstractIt has recently been proposed that a single dimension, called the p factor, can capture a person’s liability to mental disorder. Relevant to the p hypothesis, recent genetic research has found surprisingly high genetic correlations between pairs of psychiatric disorders. Here, for the first time we compare genetic correlations from different methods and examine their support for a genetic p factor. We tested the hypothesis of a genetic p factor by using principal component analysis on matrices of genetic correlations between major psychiatric disorders estimated by three methods – family study, Genome-wide Complex Trait Analysis, and Linkage-Disequilibrium Score Regression – and on a matrix of polygenic score correlations constructed for each individual in a UK-representative sample of 7,026 unrelated individuals. All disorders loaded on a first unrotated principal component, which accounted for 57%, 43%, 34% and 19% of the variance respectively for each method. Our results showed that all four methods provided strong support for a genetic p factor that represents the pinnacle of the hierarchical genetic architecture of psychopathology.

scholarly journals Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Rona J. Strawbridge ◽  
Joey Ward ◽  
Breda Cullen ◽  
Elizabeth M. Tunbridge ◽  
Sarah Hartz ◽  
...  
Keyword(s):  
Risk Taking ◽  
Genetic Correlations ◽  
Uk Biobank ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
The Uk

scholarly journals Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis

2020 ◽  
Vol 8 (1) ◽  
pp. e001140
Author(s):  
Xinpei Wang ◽  
Jinzhu Jia ◽  
Tao Huang
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Correlation ◽  
Genetic Architecture ◽  
Large Scale ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Shared Genetic

ObjectiveWe aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).Research design and methodsOur study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits.ResultsWe found positive genetic correlations between leptin levels and T2D (Rg=0.3165, p=0.0227), fasting insulin (FI) (Rg=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (Rg=0.4785, p=0.0196), as well as surrogate estimates of β-cell function (HOMA-β) (Rg=0.4456, p=0.0214). We identified 12 shared loci between leptin levels and T2D, 1 locus between leptin levels and FI, 1 locus between leptin levels and HOMA-IR, and 1 locus between leptin levels and HOMA-β. We newly identified eight loci that did not achieve genome-wide significance in trait-specific genome-wide association studies. These shared genes were enriched in pancreas, thyroid gland, skeletal muscle, placenta, liver and cerebral cortex. In addition, we found that 1-SD increase in HOMA-IR was causally associated with a 0.329 ng/mL increase in leptin levels (β=0.329, p=0.001).ConclusionsOur results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

GENOME-WIDE ANALYSIS OF RISK-TAKING BEHAVIOUR IN 116 255 INDIVIDUALS FROM THE UK BIOBANK COHORT AND CROSS-DISORDER GENETIC CORRELATIONS

2019 ◽  
Vol 29 ◽  
pp. S981-S982
Author(s):  
Rona Strawbridge ◽  
Joey Ward ◽  
Breda Cullen ◽  
Elizabeth Tunbridge ◽  
Sarah Hartz ◽  
...  
Keyword(s):  
Risk Taking ◽  
Genetic Correlations ◽  
Uk Biobank ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
The Uk

scholarly journals Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

2021 ◽  
Author(s):  
Sandra Sanchez-Roige ◽  
Pierre Fontanillas ◽  
Mariela V. Jennings ◽  
Sevim B. Bianchi ◽  
Yuye Huang ◽  
...  
Keyword(s):  
Association Study ◽  
Risk Taking ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Opioid Use ◽  
Research Participants ◽  
Genome Wide

AbstractThe growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids ‘not as prescribed’. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (rg = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg = 0.74), smoking initiation (rg = 0.63), pain relief medication intake (rg = 0.49), major depressive disorder (rg = 0.44), chronic pain (rg = 0.42), insomnia (rg = 0.39), and loneliness (rg = 0.28). Although POU was positively genetically correlated with risk-taking (rg = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

scholarly journals Genome-Wide Association Studies Dissect the G×E Interaction for Agronomic Traits in a Worldwide Collection of Safflower (Carthamus Tinctorius L.)

2021 ◽  
Author(s):  
Huanhuan Zhao ◽  
Keith W. Savin ◽  
Yongjun Li ◽  
Edmond J Breen ◽  
Pankaj Maharjan ◽  
...  
Keyword(s):  
Water Stress ◽  
Genetic Architecture ◽  
Agronomic Traits ◽  
Association Studies ◽  
Genetic Correlations ◽  
Carthamus Tinctorius ◽  
Genome Wide Association ◽  
Oil Yield ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background: Safflower (Carthamus tinctorius L.) has been cultivated worldwide for centuries, originally as a source of textile dyes. Modern safflower breeding has focused on high grain and oil yield and broad adaptability. Here, a genome-wide association study was conducted using a globally diverse Genebank collection of 406 accessions, which included landraces, breeding lines and elite cultivars. We explored the genetic architecture and genotype-by-environment interaction (G × E) patterns of grain yield (YP), days to flowering (DF ), plant height (PH), 500 seed weight (SW), seed oil content (OL), and crude protein content (PR) in four environments (sites) that differed in water availability. Results: Phenotypic variation within the global collection was observed for all traits under differed water stress environments. Two mixed linear models were adopted, and YP exhibited low overall genetic correlations (rGoverall) across sites, while SW and OL had high rGoverall and high pairwise genetic correlations (rGij) across all pairwise sites. Ninety-two marker-trait associations (MTAs) were identified using three methods, single locus genome-wide association studies (GWAS) using a mixed linear model (MLM), the Bayesian multi-locus method (BayesR), and meta-GWAS. MTAs with large effects across all sites were detected for OL, SW, and PR, and MTAs specific for the different water stress sites was identified for all traits. Five MTAs were associated with multiple traits, 4 of 5 MTAs were variously associated with the three traits of SW, OL, and PR and marker effects were consistent with phenotypic observations in different environments. The thresholds of different GWAS methods used in the study affected the number of MTAs identified for complex traits. Conclusions: This study provided insights into the phenotypic variability and genetic architecture of important safflower agronomic traits under different environments. This knowledge is essential to breed for high grain and oil yield and local adaption in safflower.

scholarly journals The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

2019 ◽  
Author(s):  
Sara Bandres-Ciga ◽  
Sarah Ahmed ◽  
Marya S. Sabir ◽  
Cornelis Blauwendraat ◽  
Astrid D. Adarmes-Gómez ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Age At Onset ◽  
Genetic Correlations ◽  
Risk Haplotype ◽  
Specific Risk ◽  
Genome Wide ◽  
Gwas Signal

ABSTRACTBackgroundThe Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.ObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.MethodsWe performed a GWAS for both risk of PD and age-at-onset (AAO) in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations and burden analyses.ResultsWe identified a novel population-specific GWAS signal atPARK2associated with AAO. We replicated four genome-wide independent signals associated with PD risk, includingSNCA, LRRK2, KANSL1/MAPTandHLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence via two-sample Mendelian randomization in expression and methylation datasets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.ConclusionsOur data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points toPARK2as a major hallmark of PD etiology in Spain.

scholarly journals Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

2021 ◽  
Author(s):  
Sandra Sanchez-Roige ◽  
Pierre Fontanillas ◽  
Mariela V Jennings ◽  
Sevim Bianchi ◽  
Yuye Huang ◽  
...  
Keyword(s):  
Association Study ◽  
Risk Taking ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Opioid Use ◽  
Research Participants ◽  
Genome Wide

Rates of opioid use disorder (OUD) constitute an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using opioids "not as prescribed". We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU; "ever taking opioid prescriptions not as prescribed") in 132,113 23andMe research participants of European ancestry (Ncases=27,805). Our GWAS identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed a positive genetic correlation with opioid dependence and OUD, as measured in the largest available GWAS (rg=0.57-0.80). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg=0.74), smoking initiation (rg=0.63), pain relief medication intake (rg=0.49), major depressive disorder (rg=0.44), chronic pain (rg=0.42), insomnia (rg=0.39), and loneliness (rg=0.28). Although POU was positively genetically correlated with risk-taking (rg=0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a general tendency for risky behavior. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

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