Dataset Information

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

ABSTRACT:

Background

The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.

Methods

Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (r_g < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.

Results

We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior).

Conclusions

Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.

SUBMITTER: Martin J

PROVIDER: S-EPMC8163257 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Martin Joanna J Khramtsova Ekaterina A EA Goleva Slavina B SB Blokland Gabriëlla A M GAM Traglia Michela M Walters Raymond K RK Hübel Christopher C Coleman Jonathan R I JRI Breen Gerome G Børglum Anders D AD Demontis Ditte D Grove Jakob J Werge Thomas T Bralten Janita J Bulik Cynthia M CM Lee Phil H PH Mathews Carol A CA Peterson Roseann E RE Winham Stacey J SJ Wray Naomi N Edenberg Howard J HJ Guo Wei W Yao Yin Y Neale Benjamin M BM Faraone Stephen V SV Petryshen Tracey L TL Weiss Lauren A LA Duncan Laramie E LE Goldstein Jill M JM Smoller Jordan W JW Stranger Barbara E BE Davis Lea K LK

Biological psychiatry 20210109 12

<h4>Background</h4>The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.<h4>Methods</h4>Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability ...[more]

PMID: 33648717

Similar Datasets

Project description:BackgroundThe corpus callosum (CC) is a brain structure with a high heritability and potential role in psychiatric disorders. However, the genetic architecture of the CC and the genetic link with psychiatric disorders remain largely unclear. We investigated the genetic architectures of the volume of the CC and its subregions and the genetic overlap with psychiatric disorders.MethodsWe applied multivariate genome-wide association study (GWAS) to genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank, aiming to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) obtained by FreeSurfer 7.1. Multivariate GWAS was run combining all subregions, co-varying for relevant variables. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression (LDSC) was used to determine Single nucleotide polymorphism (SNP)-based heritability of total CC volume and volumes of its subregions as well as their genetic correlations with relevant psychiatric traits.ResultsWe identified 70 independent loci with distributed effects across the five subregions of the CC (p < 5 × 10-8). Additionally, we identified 33 significant loci in the anterior subregion, 23 in the mid-anterior, 29 in the central, 7 in the mid-posterior and 56 in the posterior subregion. Gene-set analysis revealed 156 significant genes contributing to volume of the CC subregions (p < 2.6 × 10-6). LDSC estimated the heritability of CC to (h2SNP = 0.38, SE = 0.03) and subregions ranging from 0.22 (SE = 0.02) to 0.37 (SE = 0.03). We found significant genetic correlations of total CC volume with bipolar disorder (BD, rg = -0.09, SE = 0.03; p = 5.9 × 10-3) and drinks consumed per week (rg = -0.09, SE = 0.02; p = 4.8 × 10-4), and volume of the mid-anterior subregion with BD (rg = -0.12, SE = 0.02; p = 2.5 × 10-4), major depressive disorder (MDD) (rg = -0.12, SE = 0.04; p = 3.6 × 10-3), drinks consumed per week (rg = -0.13, SE = 0.04; p = 1.8 × 10-3) and cannabis use (rg = -0.09, SE = 0.03; p = 8.4 × 10-3).ConclusionsOur results demonstrate that the CC has a polygenic architecture implicating multiple genes and show that CC subregion volumes are heritable. We found that distinct genetic factors are involved in the development of anterior and posterior subregions, consistent with their divergent functional specialisation. Significant genetic correlation between volumes of the CC and BD, drinks per week, MDD and cannabis consumption subregion volumes with psychiatric traits is noteworthy and deserving of further investigation.

Project description:BackgroundThe hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential.MethodsWe analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits.ResultsOur analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10-9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P < 0.05/240), revealing 433 pleiotropic loci. Particularly, genes like ACBD4, ARHGAP27, KANSL1, MAPT, ARL17A, and ARL17B were involved in over 50 HASV-neuropsychiatric pairs. Leveraging Mendelian randomization analysis, we further confirmed that atrophy in the left hippocampus, right hippocampus, right hippocampal body, and right CA1-3 region were associated with an increased risk of developing Parkinson's disease (PD). Furthermore, PRS for all four HASVs were significantly linked to a higher risk of Parkinson's disease (PD), with the highest hazard ratio (HR) of 1.30 (95% CI 1.18-1.43, P = 6.15 × 10⁻⁸) for right hippocampal volume.ConclusionsThese findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages.

Dataset Information

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Background

Methods

Results

Conclusions

Publications

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets