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

38 Citations (Scopus)

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.

Original language	English
Journal	Biological Psychiatry
Volume	89
Issue number	12
Pages (from-to)	1127-1137
Number of pages	11
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2020.12.024
Publication status	Published - 15 Jun 2021

Keywords

Female
Genome-Wide Association Study
Humans
Male
Multifactorial Inheritance
Phenotype
Polymorphism, Single Nucleotide
Sex Characteristics

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10.1016/j.biopsych.2020.12.024

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@article{00cb51eef48546998c73434ea499b746,

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 = "Female, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Sex Characteristics",

author = "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 {Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium}",

year = "2021",

month = jun,

day = "15",

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

language = "English",

volume = "89",

pages = "1127--1137",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc",

number = "12",

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TY - JOUR

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

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

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 - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Multifactorial Inheritance

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Sex Characteristics

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

U2 - 10.1016/j.biopsych.2020.12.024

DO - 10.1016/j.biopsych.2020.12.024

M3 - Journal article

C2 - 33648717

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

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Keywords

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