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Exploring Interactions Between Genotype and Sex on the Risk of Psychiatric Disorders

Key findings

  • In the largest study to date, genome-wide genotype-by-sex interactions that influence risk of schizophrenia, major depressive disorder and bipolar disorder were tested, using 85,735 cases and 109,946 controls from the Psychiatric Genomics Consortium and iPSYCH cohort Denmark
  • Several loci showed significant genotype-by-sex interaction effects across and within disorders: NKAIN2 and AMIGO1/GPR61 at the variant level, SLTM and IDO2 and ZNF385C at the gene level and VEGF and MOCOS (vascular signaling) at the pathway level
  • These findings implicate neuronal excitability and regulation of brain development and functioning, as well as immune and vascular pathways
  • Several genes that regulate neuronal excitability and immune function had opposite effects on the risk of these psychiatric disorders by sex
  • Additional large-scale genetic studies that have the statistical power to test for interactions with sex will might identify targets for sex-dependent or sex-specific therapeutic interventions

Age at onset, course and prognosis vary considerably by sex in schizophrenia, major depressive disorder (MDD) and bipolar disorder (BPD). Moreover, women have a significantly higher incidence of MDD than men but a lower incidence of schizophrenia.

Genome-wide association studies (GWAS) have detected sex differences in the genetic risk of all three disorders. However, most have reported sex-stratified associations, which are sufficient only if it can be assumed there are no interactions between covariates and sex. Since this is unlikely, genotype-by-sex interaction analysis is necessary to identify significant sex differences.

Massachusetts General Hospital researchers recently led the largest genome-wide genotype-by-sex interaction analysis of mood and psychotic disorders to date. They found significant sex-dependent effects were enriched for genes related to neuronal development, immune function and vascular function across and within schizophrenia, MDD and BPD.

The findings are reported in Biological Psychiatry by Gabriëlla A.M. Blokland, PhD, former postdoc at the Center for Genomic Medicine at Mass General, and Jordan W. Smoller, MD, ScD, director of the Psychiatric and Neurodevelopmental Genetics Unit in the Department of Psychiatry at Mass General; and senior author Jill M. Goldstein, PhD, MPH, executive director of the Innovation Center on Sex Differences in Medicine and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women's Health; and colleagues.

Study Cohorts

The researchers analyzed data on 195,681 individuals:

  • Psychiatric Genomics Consortium—43 schizophrenia cohorts (30,608 patients, 38,441 controls); 26 MDD cohorts (15,970 patients, 24,984 controls); 28 BPD cohorts (18,958 patients, 29,996 controls)
  • iPSYCH cohort in Denmark—2,795 patients with schizophrenia and 2,436 controls; 16,438 patients with MDD and 13,538 controls; 966 patients with BPD and 551 controls

All cohorts were of European ancestry except for three East Asian schizophrenia cohorts.

Sex-stratified GWAS

  • Autosomal sex-specific SNP-based heritability estimates—Substantially different between the sexes for schizophrenia and MDD but not BPD
  • SNP-based genetic correlations across disorders—No significant differences by sex except between BPD and MDD
  • SNP-based genetic correlations within sexes—Women with schizophrenia and women with BPD were more highly correlated than women with schizophrenia and women with MDD; men with schizophrenia were correlated with men with BPD but men with MDD and men with BPD were uncorrelated

Genome-wide SNP-by-Sex Interactions

Analyses within disorders did not detect genome-wide significant genotype-by-sex interactions for schizophrenia, MDD or BPD. However, tests across disorders revealed several loci; the top two were:

  • NKAIN2 in schizophrenia and BPD. The minor allele was linked to increased risk in women with schizophrenia and decreased risk in men with schizophrenia, and the opposite was true in women and men with BPD. NKAIN2 is expressed in the brain and has been shown to regulate neuronal excitability and CNS differentiation, and it has been associated with cognitive ability.
  • AMIGO1/GPR61 (neuronal excitability) in MDD and BPD. Again, the effect was opposite; the minor allele had stronger effects in women with BPD and weaker effects in women with MDD versus men. Like NKAIN2, AMIGO1/GPR61 regulates neuronal excitability.

Gene- and Pathway-based Analyses

  • A genotype-by-sex interaction of SLTM (transcriptional inhibition) within schizophrenia approached statistical significance; SLTM is a general inhibitor of transcription that is highly expressed in certain brain regions
  • Within MDD, genotype-by-sex SNPs were significantly enriched in genes that regulate vascular endothelial growth factor (VEGF) receptor signaling; this is interesting since cardiovascular disease is often comorbid with schizophrenia and MDD (and the latter risk is higher in women)
  • Immune pathway dysregulation (IDO2 in schizophrenia) demonstrated opposite genetic effects by sex and sex differences in immune-related ZNF385C (immune mechanisms) were found in MDD.

Therapeutic Implications

These findings are consistent with previous transcriptomics research that demonstrated sexually dimorphic expression in the brain of a substantial proportion of autosomal genes related to fundamental neural functions. Additional large-scale genetic studies that have the statistical power to test for interactions with sex might identify targets for sex-dependent or sex-specific therapeutic interventions.

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