Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

doi:10.1016/j.biopsych.2020.12.024

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1127-1137
Number of pages	11
Journal	Biological psychiatry
Volume	89
Issue number	12
DOIs	https://doi.org/10.1016/j.biopsych.2020.12.024
State	Published - Jun 15 2021

Keywords

Behavioral
GWAS
Genetic correlation
Heritability
Psychiatric
Sex differences

ASJC Scopus subject areas

Biological Psychiatry

Access to Document

10.1016/j.biopsych.2020.12.024

Cite this

@article{41989ccd4015421a9a999657124a7d01,

title = "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 (rg < 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.",

keywords = "Behavioral, GWAS, Genetic correlation, Heritability, Psychiatric, Sex differences",

author = "{Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium} and Joanna Martin and Khramtsova, {Ekaterina A.} and Goleva, {Slavina B.} and Blokland, {Gabri{\"e}lla A.M.} and Michela Traglia and Walters, {Raymond K.} and Christopher H{\"u}bel and Coleman, {Jonathan R.I.} and Gerome Breen and B{\o}rglum, {Anders D.} and Ditte Demontis and Jakob Grove and Thomas Werge and Janita Bralten and Bulik, {Cynthia M.} and Lee, {Phil H.} and Mathews, {Carol A.} and Peterson, {Roseann E.} and Winham, {Stacey J.} and Naomi Wray and Edenberg, {Howard J.} and Wei Guo and Yin Yao and Neale, {Benjamin M.} and Faraone, {Stephen V.} and Petryshen, {Tracey L.} and Weiss, {Lauren A.} and Duncan, {Laramie E.} and Goldstein, {Jill M.} and Smoller, {Jordan W.} and Stranger, {Barbara E.} and Davis, {Lea K.} and Martin Alda and Marco Bortolato and Burton, {Christie L.} and Enda Byrne and Carey, {Caitlin E.} and Lauren Erdman and Huckins, {Laura M.} and Manuel Mattheisen and Elise Robinson and Eli Stahl",

note = "Publisher Copyright: {\textcopyright} 2021 Society of Biological Psychiatry",

year = "2021",

month = jun,

day = "15",

doi = "10.1016/j.biopsych.2020.12.024",

language = "English (US)",

volume = "89",

pages = "1127--1137",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "12",

}

TY - JOUR

T1 - Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

AU - Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

AU - Martin, Joanna

AU - Khramtsova, Ekaterina A.

AU - Goleva, Slavina B.

AU - Blokland, Gabriëlla A.M.

AU - Traglia, Michela

AU - Walters, Raymond K.

AU - Hübel, Christopher

AU - Coleman, Jonathan R.I.

AU - Breen, Gerome

AU - Børglum, Anders D.

AU - Demontis, Ditte

AU - Grove, Jakob

AU - Werge, Thomas

AU - Bralten, Janita

AU - Bulik, Cynthia M.

AU - Lee, Phil H.

AU - Mathews, Carol A.

AU - Peterson, Roseann E.

AU - Winham, Stacey J.

AU - Wray, Naomi

AU - Edenberg, Howard J.

AU - Guo, Wei

AU - Yao, Yin

AU - Neale, Benjamin M.

AU - Faraone, Stephen V.

AU - Petryshen, Tracey L.

AU - Weiss, Lauren A.

AU - Duncan, Laramie E.

AU - Goldstein, Jill M.

AU - Smoller, Jordan W.

AU - Stranger, Barbara E.

AU - Davis, Lea K.

AU - Alda, Martin

AU - Bortolato, Marco

AU - Burton, Christie L.

AU - Byrne, Enda

AU - Carey, Caitlin E.

AU - Erdman, Lauren

AU - Huckins, Laura M.

AU - Mattheisen, Manuel

AU - Robinson, Elise

AU - Stahl, Eli

PY - 2021/6/15

Y1 - 2021/6/15

N2 - 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 (rg < 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.

AB - 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 (rg < 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.

KW - Behavioral

KW - GWAS

KW - Genetic correlation

KW - Heritability

KW - Psychiatric

KW - Sex differences

UR - http://www.scopus.com/inward/record.url?scp=85102837416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85102837416&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2020.12.024

DO - 10.1016/j.biopsych.2020.12.024

M3 - Article

C2 - 33648717

AN - SCOPUS:85102837416

SN - 0006-3223

VL - 89

SP - 1127

EP - 1137

JO - Biological psychiatry

JF - Biological psychiatry

IS - 12

ER -

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this