Cross‐sex shifts in two brain imaging phenotypes and their relation to polygenic scores for same‐sex sexual behavior: A study of 18,645 individuals from the UK Biobank

Genetic and hormonal factors have been suggested to influence human sexual orientation. Previous studied proposed brain differences related to sexual orientation and that these follow cross‐sex shifted patterns. However, the neurobiological correlates of sexual orientation and how genetic factors relate to brain structural variation remains largely unexplored. Using the largest neuroimaging‐genetics dataset available on same‐sex sexual behavior (SSB) (n = 18,645), we employed a data‐driven multivariate classification algorithm (PLS) on magnetic resonance imaging data from two imaging modalities to extract brain covariance patterns related to sex. Through analyses of latent variables, we tested for SSB‐related cross‐sex shifts in such patterns. Using genotype data, polygenic scores reflecting the genetic predisposition for SSB were computed and tested for associations with neuroimaging outcomes. Patterns important for classifying between males and females were less pronounced in non‐heterosexuals. Predominantly in non‐heterosexual females, multivariate brain patterns as represented by latent variables were shifted toward the opposite sex. Complementary univariate analyses revealed region specific SSB‐related differences in both males and females. Polygenic scores for SSB were associated with volume of lateral occipital and temporo‐occipital cortices. The present large‐scale study demonstrates multivariate neuroanatomical correlates of SSB, and tentatively suggests that genetic factors related to SSB may contribute to structural variation in certain brain structures. These findings support a neurobiological basis to the differences in human sexuality.

[1]  L. Jäncke.  Faculty Opinions recommendation of Cross-sex shifts in two brain imaging phenotypes and their relation to polygenic scores for same-sex sexual behavior: A study of 18,645 individuals from the UK Biobank. , 2021, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[2]  Christian Gaser,et al.  Development of sex differences in the human brain , 2020, Cognitive neuroscience.

[3]  M. Allen,et al.  Personality and Sexual Orientation: New Data and Meta-analysis , 2020, Journal of sex research.

[4]  I. Deary,et al.  Impact of Polygenic Risk for Schizophrenia on Cortical Structure in UK Biobank , 2019, Biological Psychiatry.

[5]  Brendan P. Zietsch,et al.  Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior , 2019, Science.

[6]  S. Norton,et al.  Early life conditions and adolescent sexual orientation: A prospective birth cohort study. , 2019, Developmental psychology.

[7]  V. Calhoun,et al.  Machine learning of brain gray matter differentiates sex in a large forensic sample , 2018, Human brain mapping.

[8]  Kevin A. Rosenfield,et al.  Organizational effects of hormones on sexual orientation , 2018, Routledge International Handbook of Social Neuroendocrinology.

[9]  A. Manzouri,et al.  Multimodal MRI suggests that male homosexuality may be linked to cerebral midline structures , 2018, PloS one.

[10]  J. Marchini,et al.  Genome-wide association studies of brain imaging phenotypes in UK Biobank , 2018, Nature.

[11]  Timothy Shin Heng Mak,et al.  Tutorial: a guide to performing polygenic risk score analyses , 2018, bioRxiv.

[12]  M. Ingvar,et al.  Cortical brain structure and sexual orientation in adult females with bipolar disorder or attention deficit hyperactivity disorder , 2018, Brain and behavior.

[13]  A. Manzouri,et al.  Cerebral sex dimorphism and sexual orientation , 2018, Human brain mapping.

[14]  A. Manzouri,et al.  Structural connections in the brain in relation to gender identity and sexual orientation , 2017, Scientific Reports.

[15]  Georgia G. Gregoriou,et al.  Top-Down Control of Visual Attention by the Prefrontal Cortex. Functional Specialization and Long-Range Interactions , 2017, Front. Neurosci..

[16]  S. Norton,et al.  Sexual orientation and neurocognitive ability: A meta-analysis in men and women , 2017, Neuroscience & Biobehavioral Reviews.

[17]  Ludovica Griffanti,et al.  Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank , 2017, NeuroImage.

[18]  M. Hines,et al.  Childhood Gender-Typed Behavior and Adolescent Sexual Orientation: A Longitudinal Population-Based Study , 2017, Developmental psychology.

[19]  R. Bränström.  Minority stress factors as mediators of sexual orientation disparities in mental health treatment: a longitudinal population-based study , 2017, Journal of Epidemiology & Community Health.

[20]  P. Matthews,et al.  Multimodal population brain imaging in the UK Biobank prospective epidemiological study , 2016, Nature Neuroscience.

[21]  E. Vilain,et al.  Sexual Orientation, Controversy, and Science , 2016, Psychological science in the public interest : a journal of the American Psychological Society.

[22]  D. K. Marcus,et al.  Homosexuality as a Discrete Class , 2015, Psychological science.

[23]  P. Tremblay,et al.  Mental health of sexual minorities. A systematic review , 2015, International review of psychiatry.

[24]  T. Spector,et al.  Common genetic factors among sexual orientation, gender nonconformity, and number of sex partners in female twins: implications for the evolution of homosexuality. , 2015, The journal of sexual medicine.

[25]  R. de Graaf,et al.  Same-sex sexuality and psychiatric disorders in the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). , 2014, LGBT health.

[26]  C. Abé,et al.  Sexual Orientation Related Differences in Cortical Thickness in Male Individuals , 2014, PloS one.

[27]  G. Gates.  LGBT Demographics: Comparisons among population-based surveys , 2014 .

[28]  C. Aguilar,et al.  Multivariate classification of patients with Alzheimer’s and dementia with Lewy bodies using high-dimensional cortical thickness measurements: an MRI surface-based morphometric study , 2013, Journal of Neurology.

[29]  H. Möller,et al.  Multivariate patterns of brain–cognition associations relating to vulnerability and clinical outcome in the at‐risk mental states for psychosis , 2012, Human brain mapping.

[30]  P. Elliott,et al.  UK Biobank: Current status and what it means for epidemiology , 2012 .

[31]  M. Kringelbach,et al.  The human sexual response cycle: Brain imaging evidence linking sex to other pleasures , 2012, Progress in Neurobiology.

[32]  M. Hines,et al.  Gender development and the human brain. , 2011, Annual review of neuroscience.

[33]  Anthony Randal McIntosh,et al.  Partial Least Squares (PLS) methods for neuroimaging: A tutorial and review , 2011, NeuroImage.

[34]  G. Gates,et al.  How Many People are Lesbian, Gay, Bisexual and Transgender? , 2011 .

[35]  Nicholas A. Steinmetz,et al.  Top-down control of visual attention , 2010, Current Opinion in Neurobiology.

[36]  P. Lichtenstein,et al.  Genetic and Environmental Effects on Same-sex Sexual Behavior: A Population Study of Twins in Sweden , 2010, Archives of sexual behavior.

[37]  Q. Rahman,et al.  Psychiatric morbidity associated with same-sex sexual behaviour: influence of minority stress and familial factors , 2009, Psychological Medicine.

[38]  Ivanka Savic,et al.  PET and MRI show differences in cerebral asymmetry and functional connectivity between homo- and heterosexual subjects , 2008, Proceedings of the National Academy of Sciences.

[39]  Stefan Klöppel,et al.  Homosexual Women Have Less Grey Matter in Perirhinal Cortex than Heterosexual Women , 2007, PloS one.

[40]  A. Cavanna,et al.  The precuneus: a review of its functional anatomy and behavioural correlates. , 2006, Brain : a journal of neurology.

[41]  Q. Rahman.  The neurodevelopment of human sexual orientation , 2005, Neuroscience & Biobehavioral Reviews.

[42]  R. Kessler,et al.  Sexual orientation in a U.S. national sample of twin and nontwin sibling pairs. , 2000, The American journal of psychiatry.

[43]  C. Gilbert,et al.  Attention and primary visual cortex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M F Huque,et al.  Some comments on frequently used multiple endpoint adjustment methods in clinical trials. , 1997, Statistics in medicine.

[45]  S. Levay,et al.  A difference in hypothalamic structure between heterosexual and homosexual men , 1991, Science.

[46]  S. Wold,et al.  The Collinearity Problem in Linear Regression. The Partial Least Squares (PLS) Approach to Generalized Inverses , 1984 .

[47]  Alicia Garcia-Falgueras,et al.  Sexual differentiation of the human brain in relation to gender identity and sexual orientation. , 2009, Functional neurology.

[48]  L. Gygax,et al.  Sexual orientation and childhood gender nonconformity: evidence from home videos. , 2008, Developmental psychology.

[49]  R. de Graaf,et al.  Same-sex sexual behavior and psychiatric disorders: findings from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). , 2001, Archives of general psychiatry.

[50]  H. Martens,et al.  Modified Jack-knife estimation of parameter uncertainty in bilinear modelling by partial least squares regression (PLSR) , 2000 .

[51]  N. Martin,et al.  Genetic and environmental influences on sexual orientation and its correlates in an Australian twin sample. , 2000, Journal of personality and social psychology.

[52]  J. Bailey,et al.  Childhood sex-typed behavior and sexual orientation: A conceptual analysis and quantitative review. , 1995 .

[53]  J. Michael.  Childhood Sex-Typed Behavior and Sexual Orientation: A Conceptual Analysis and Quantitative Review (Special Issue: Sexual Orientation and Human Development) , 1995 .

[54]  E. Maccoby,et al.  The development of sex differences , 1966 .