Sex differences in the genetic architecture of obsessive-compulsive disorder.
paper
Cited
Public
- Authors
- Khramtsova, Ekaterina A; Heldman, Raphael; Derks, Eske M; Yu, Dongmei; Tourette Syndrome/Obsessive-Compulsive Disorder Working Group of the Psychiatric Genomics Consortium; Davis, Lea K; Stranger, Barbara E
- Year
- 2019
- Journal
- American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
- PMID
- 30456828
- DOI
- 10.1002/ajmg.b.32687
- PMCID
- PMC6527502
Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex-dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex-combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD.
Manhattan and quantile-quantile plots for sex-stratified meta-GWAS. Meta-GWAS was run separately for females (1525 cases and 4307 controls) and males (1249 cases and 2789 controls) on ~5.5 million imputed SNPs (MAF>5%). (A) The peaks pointing up on the plot are the results for female analysis and the peaks pointing down are the results for male analysis. Although not genome-wide significant, several suggestive peaks can be observed in one sex and not observed in the other. (B) Quantile-quantile plot for sex-stratified and combined meta-GWAS. (C) Scatter plot of -log10(p-value) for female OCD assications (x-axis) versus male OCD associations (y-axis). Contour lines colored from red to blue indicate decreasing data density.
eQTL enrichment in the brain and immune tissues for combined, female-specific, male-specific top associations (10−3) and SNPs with Sexually Differentiated Effect SNPs (SDEs), excluding and including SNPs in the HLA region. Only variants with more than 500 individuals in the GWAS are included here. Light green bars represent each immune tissue or cell type: whole blood, monocytes, and cd4+ T cells, while the dark green represents enrichment in a combination of the three immune tissues. Light blue bars represent each brain tissue, while the dark blue represents enrichment in a combination of ten brain tissues, or all ten brain tissues minus cerebellum. The black dashed line represents a p-value of 0.05. The red dashed line represents the significant p-value threshold (0.00357) after accounting for 14 eQTL datasets tested.
| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| 1000 Genomes Project Phase 3 European population local | cohort |
| 10 regions of the brain local | anatomy |
| Accumbens Volume local | anatomy |
| ADHD | phenotype |
| adult-onset OCD local | phenotype |
| affected individuals | cohort |
| age at first birth | phenotype |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Amygdala Volume local | anatomy |
| anorexia nervosa | phenotype |
| anterior cingulate cortex | anatomy |
| anxiety | phenotype |
| ASD | phenotype |
| ASDEs local | phenotype |
| Ashkenazi Jewish ancestry | cohort |
| attention deficit hyperactivity disorder | phenotype |
| autism | phenotype |
| autism spectrum disorder | phenotype |
| autosomal SNPs | cohort |
| behavioral traits | phenotype |
| binary trait | phenotype |
| bipolar disorder | phenotype |
| BMI | phenotype |
| body mass index | phenotype |
| body weight | phenotype |
| brain | anatomy |
| brain cortex tissue local | anatomy |
| Brainstorm Consortium | cohort |
| brain structure | anatomy |
| Brain structure volumes local | anatomy |
| brain tissue | anatomy |
| Brain volumes local | phenotype |
| Cappi 2016 whole-exome sequencing study local | cohort |
| Case/control dataset local | cohort |
| caudate nucleus | anatomy |
| cerebellum | anatomy |
| Childbirth local | phenotype |
| cognition | phenotype |
| combined GWAS analysis local | cohort |
| Combined OCD sample local | cohort |
| common variants | cohort |
| Contamination and cleaning compulsions local | phenotype |
| controls | cohort |
| Davis et al. 2013 local | cohort |
| de novo nonsynonymous SNVs local | variant |
| depressive symptoms | phenotype |
| Dutch ancestry local | cohort |
| early-onset OCD local | phenotype |
| eating disorders | phenotype |
| educational attainment | phenotype |
| employment | phenotype |
| endometriosis local | phenotype |
| eQTLGen Consortium | cohort |
| European ancestry | cohort |
| European catalogue of 1000 Genomes SNPs local | cohort |
| European population | cohort |
| female-specific meta-analysis local | cohort |
| frontal cortex | anatomy |
| gene | gene |
| genotype-sex interaction test local | phenotype |
| GIANT consortium | cohort |
| GPR135 local | gene |
| Grid2 | gene |
| GTEx v7 | cohort |
| GWAS results local | phenotype |
| HapMap3 | cohort |
| height | phenotype |
| HIPadjBMI local | phenotype |
| hip circumference | phenotype |
| Hippocampal volume | anatomy |
| HLA | gene |
| immune function | phenotype |
| immune tissue local | anatomy |
| insomnia | phenotype |
| International Obsessive Compulsive Disorder Foundation Genetics Collaborative local | cohort |
| intracranial volume | anatomy |
| IOCDF-GC | cohort |
| IOCDF-GC/OCGAS 2017 GWAS local | cohort |
| lead SNP | cohort |
| MAF differences between sexes local | phenotype |
| major depressive disorder | phenotype |
| Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium local | cohort |
| male-specific meta-analysis local | cohort |
| marital status | phenotype |
| Mathis et al 2011 cohort local | cohort |
| Mattheisen et al. 2015 GWAS local | cohort |
| menopausal status | phenotype |
| meta-analysis | cohort |
| MHC region | gene |
| Nestadt et al 2010 cohort local | cohort |
| Neurodegenerative traits local | phenotype |
| neuroticism | phenotype |
| nucleus accumbens | anatomy |
| null matched SNP sets local | variant |
| number of children ever born | phenotype |
| obsessive-compulsive disorder | phenotype |
| Obsessive-compulsive symptoms | phenotype |
| OCD | phenotype |
| OCD-associated SNPs local | variant |
| OCD Collaborative Genetics Association Studies local | cohort |
| OCD probands | cohort |
| OCD Psychiatric Genomics Consortium sample local | cohort |
| OCD SDEs local | phenotype |
| OCGAS | cohort |
| Pallidum Volume local | anatomy |
| parietal cortex | anatomy |
| physical abuse | phenotype |
| Post-Traumatic Stress Disorder | phenotype |
| pregnancy | phenotype |
| Premenstrual period local | phenotype |
| Proband cases local | cohort |
| Pseudo-controls local | cohort |
| Psychiatric Genomics Consortium | cohort |
| Psychiatric GWAS Consortium Bipolar Disorder Working Group local | cohort |
| psychiatric traits | phenotype |
| putamen | anatomy |
| Putamen Volume local | anatomy |
| Religious symptoms local | phenotype |
| Reproductive behavior | phenotype |
| schizophrenia | phenotype |
| Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014 local | cohort |
| SDE local | variant |
| SDEs local | phenotype |
| SDEs local | variant |
| sex | phenotype |
| sex as covariate local | phenotype |
| sex-stratified analysis local | phenotype |
| sex-stratified GWAS analysis local | cohort |
| Sex-stratified GWAS analysis local | cohort |
| Sex-stratified OCD samples local | cohort |
| Sexually Differentiated Effect local | phenotype |
| Sexually Differentiated Effects local | variant |
| Sexual symptoms local | phenotype |
| smoking | phenotype |
| SNP | cohort |
| South African ancestry local | cohort |
| Stewart et al. 2013 GWAS local | cohort |
| Stewart et al. 2013 OCD GWAS local | cohort |
| subjective well-being | phenotype |
| Symmetry symptoms local | phenotype |
| Thalamus Volume local | anatomy |
| Tobacco and Genetics Consortium | cohort |
| Tobacco Usage local | phenotype |
| Tourette syndrome | phenotype |
| Trio data local | cohort |
| Trio samples local | cohort |
| variant | cohort |
| waist circumference | phenotype |
| waist-to-hip ratio | phenotype |
| WCadjBMI local | phenotype |
| WHRadjBMI local | phenotype |
| X chromosome | drug |
| X chromosome SNPs local | variant |
| Z-score p-values local | phenotype |
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genetic Underpinnings of Obsessive-Compulsive Disorder With and Without Tics: Implications of Genetic Heterogeneity on Clinical Management. | Zouki JJ et al. | — | 2026 | → |
| Genetic and functional analyses of CTBP2 in anorexia nervosa and body weight regulation. | Giuranna J et al. | — | 2025 | → |
| Molecular Mechanism of the <i>Grid</i> Gene Family Regulating Growth Size Heteromorphism in <i>Cynoglossus semilaevis</i>. | Wang Y et al. | — | 2025 | → |
| The Role of Epigenetics in the Pathogenesis and Potential Treatment of Obsessive-compulsive Disorder. | Peedicayil J | — | 2025 | → |
| Multivariate genetic architecture reveals testosterone-driven sexual antagonism in contemporary humans. | Chakrabarty A et al. | — | 2024 | → |
| Sex-specific genetic architecture of blood pressure. | Yang ML et al. | — | 2024 | → |
| Genetics, sex, and gender. | Reale C et al. | — | 2023 | → |
| Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa. | Rajcsanyi LS et al. | — | 2023 | → |
| Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration. | Austin-Zimmerman I et al. | — | 2023 | → |
| Mapping the neuroanatomical heterogeneity of OCD using a framework integrating normative model and non-negative matrix factorization. | Han S et al. | — | 2023 | → |
| Measurement fidelity of clinical assessment methods in a global study on identifying reproducible brain signatures of obsessive-compulsive disorder. | Shavitt RG et al. | — | 2023 | → |
| A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders. | Wang H et al. | — | 2022 | → |
| Determination of the relationship between major histocompatibility complex alleles and childhood onset obsessive-compulsive disorder. | Lüleyap Ü et al. | — | 2022 | → |
| Drosophila melanogaster hosts coevolving with Pseudomonas entomophila pathogen show sex-specific patterns of local adaptation. | Ahlawat N et al. | — | 2022 | → |
| MAOA-LPR polymorphism and math anxiety: A marker of genetic susceptibility to social influences in girls? | Carvalho MRS et al. | — | 2022 | → |
| Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene. | Pangilinan F et al. | — | 2022 | → |
| PTBP2 - a gene with relevance for both Anorexia nervosa and body weight regulation. | Zheng Y et al. | — | 2022 | → |
| Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. | Blokland GAM et al. | — | 2022 | → |
| A dimensional perspective on the genetics of obsessive-compulsive disorder. | Strom NI et al. | — | 2021 | → |
| Association of Gene Variations in Ionotropic Glutamate Receptor and Attention-Deficit/Hyperactivity Disorder in the Chinese Population: A Two-Stage Case-Control Study. | Zhang Q et al. | — | 2021 | → |
| Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits. | Martin J et al. | — | 2021 | → |
| Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants. | Halvorsen M et al. | — | 2021 | → |
| Genetic predisposition to tinnitus in the UK Biobank population. | Urbanek ME et al. | — | 2021 | → |
| Genetics of obsessive-compulsive disorder. | Mahjani B et al. | — | 2021 | → |
| Genomics of Obsessive-Compulsive Disorder-Toward Personalized Medicine in the Era of Big Data. | Szejko N et al. | — | 2021 | → |
| Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis. | Strom NI et al. | — | 2021 | → |
| The association of polygenic risk for schizophrenia, bipolar disorder, and depression with neural connectivity in adolescents and young adults: examining developmental and sex differences. | Meyers JL et al. | — | 2021 | → |
| Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation. | Ouidir M et al. | — | 2020 | → |
| Cutting-edge genetics in obsessive-compulsive disorder. | Saraiva LC et al. | — | 2020 | → |
| Heterogeneity and Polygenicity in Psychiatric Disorders: A Genome-Wide Perspective. | Wendt FR et al. | — | 2020 | → |
| Obsessive-compulsive and related disorders. | Mattina GF et al. | — | 2020 | → |
| Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders | Blokland GAM et al. | — | 2020 | — |
| Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders. | Merikangas AK et al. | — | 2020 | → |
| Association analyses reveal gender-specific associations of DAT1 40-bp VNTR and -839C/T polymorphisms with obsessive-compulsive disorder and obsessive-compulsive symptoms. | Cotrin JC et al. | — | 2019 | → |
| Conservation, acquisition, and functional impact of sex-biased gene expression in mammals. | Naqvi S et al. | — | 2019 | → |
| Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent. | Hübel C et al. | — | 2019 | → |
| Sex: a key consideration in understanding the etiology of psychiatric disorders and improving treatment | Tannenbaum C et al. | — | 2019 | → |
| Update on Sexual Dimorphism in Brain Structure-Function Interrelationships: A Literature Review. | Pallayova M et al. | — | 2019 | → |
| Bridging Molecular Genetics and Epidemiology to Better Understand Sex Differences in Attention-Deficit/Hyperactivity Disorder. | Davis LK | — | 2018 | → |