Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Joanna Martin; Ekaterina A Khramtsova; Slavina B Goleva; Gabriëlla A M Blokland; Michela Traglia; Raymond K Walters; Christopher Hübel; Jonathan R I Coleman; Gerome Breen; Anders D Børglum; Ditte Demontis; Jakob Grove; Thomas Werge; Janita Bralten; Cynthia M Bulik; Phil H Lee; Carol A Mathews; Roseann E Peterson; Stacey J Winham; Naomi Wray; Howard J Edenberg; Wei Guo; Yin Yao; Benjamin M Neale; Stephen V Faraone; Tracey L Petryshen; Lauren A Weiss; Laramie E Duncan; Jill M Goldstein; Jordan W Smoller; Barbara E Stranger; Lea K Davis; 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

Biol Psychiatry. 2021 Jun 15;89(12):1127-1137. doi: 10.1016/j.biopsych.2020.12.024. Epub 2021 Jan 9.

Authors

Joanna Martin¹, Ekaterina A Khramtsova², Slavina B Goleva³, Gabriëlla A M Blokland⁴, Michela Traglia⁵, Raymond K Walters⁶, Christopher Hübel⁷, Jonathan R I Coleman⁸, Gerome Breen⁸, Anders D Børglum⁹, Ditte Demontis⁹, Jakob Grove⁹, Thomas Werge¹⁰, Janita Bralten¹¹, Cynthia M Bulik¹², Phil H Lee¹³, Carol A Mathews¹⁴, Roseann E Peterson¹⁵, Stacey J Winham¹⁶, Naomi Wray¹⁷, Howard J Edenberg¹⁸, Wei Guo¹⁹, Yin Yao²⁰, Benjamin M Neale²¹, Stephen V Faraone²², Tracey L Petryshen¹³, Lauren A Weiss⁵, Laramie E Duncan²³, Jill M Goldstein²⁴, Jordan W Smoller²⁵, Barbara E Stranger²⁶, Lea K Davis²⁷; Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

Collaborators

Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium:
Martin Alda, Marco Bortolato, Christie L Burton, Enda Byrne, Caitlin E Carey, Lauren Erdman, Laura M Huckins, Manuel Mattheisen, Elise Robinson, Eli Stahl

Affiliations

¹ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: martinjm1@cardiff.ac.uk.
² Section of Genetic Medicine, Department of Medicine and Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois; Computational Sciences, Janssen Pharmaceuticals, Spring House, Pennsylvania.
³ Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee.
⁴ Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands.
⁵ Department of Psychiatry, University of California San Francisco, San Francisco, California; Institute for Human Genetics, University of California San Francisco, San Francisco, California; Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California.
⁶ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁸ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; National Institute for Health Research Maudsley Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, United Kingdom.
⁹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
¹⁰ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen, Denmark; Section for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark.
¹¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹² Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹³ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁴ Department of Psychiatry, University of Florida, Gainesville, Florida; Genetics Institute, University of Florida, Gainesville, Florida.
¹⁵ Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
¹⁶ Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
¹⁷ Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
¹⁸ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
¹⁹ Genetic Epidemiology Research Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
²⁰ School of Life Sciences, Fudan University, Shanghai, China.
²¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
²² Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, New York; Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York.
²³ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
²⁴ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
²⁵ Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
²⁶ Section of Genetic Medicine, Department of Medicine and Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois; Center for Genetic Medicine, Department of Pharmacology, Northwestern University, Chicago, Illinois.
²⁷ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: lea.k.davis@gmail.com.

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.

Keywords: Behavioral; GWAS; Genetic correlation; Heritability; Psychiatric; Sex differences.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Abstract

Publication types

MeSH terms

Grants and funding