“Common and Rare Variant Associations With Latent Traits Underlying Depression, Bipolar Disorder, and Schizophrenia”, 2023-02-06 ():
Genetic studies in psychiatry have primarily focused on the effects of common genetic variants, but few have investigated the role of rare genetic variants, particularly for major depression. In order to explore the role of rare variants in the gap between estimates of SNP heritability and twin study heritability, we examined the contribution of common and rare genetic variants to latent traits underlying psychiatric disorders using high-quality imputed genotype data from the UK Biobank.
Using a pre-registered analysis, we used items from the UK Biobank Mental Health Questionnaire relevant to 3 psychiatric disorders: major depression (n = 134,463), bipolar disorder (n = 117,376) and schizophrenia (n = 130,013) and identified a general hierarchical factor for each that described participants’ responses. We calculated participants’ scores on these latent traits and conducted single-variant genetic association testing (MAF > 0.05%), gene-based burden testing and pathway association testing associations with these latent traits. We tested for enrichment of rare variants (MAF 0.05–1%) in genes that had been previously identified by common variant genome-wide association studies, and genes previously associated with Mendelian disorders having relevant symptoms.
We found moderate genetic correlations between the latent traits in our study and case-control phenotypes in previous genome-wide association studies, and identified one common genetic variant (rs72657988, minor allele frequency = 8.23%, p = 1.01 × 10−9) associated with the general factor of schizophrenia, but no other single variants, genes or pathways passed statistical-significance thresholds in this analysis, and we did not find enrichment in previously identified genes.
…We found moderate genetic correlations between the latent traits we derived from reported symptoms and case-control phenotypes from previous studies. We noted that, for schizophrenia, the genetic correlation between the latent trait and the case-control phenotype was low, while it was moderate for bipolar disorder and much higher for depression (Table 1). We found high genetic correlations between all 3 latent traits and the case-control phenotype of depression (Table S23). Previous studies62, 63 have also found higher genetic correlations between psychotic experiences and depression than schizophrenia, although the mechanisms are unclear.
Additionally, heritability estimates were lower in latent traits in the UK Biobank compared to case-control phenotypes from previous GWAS (Table 1). This may be partly due to the characteristics of the sample, as participants in the UK Biobank and Mental Health Questionnaire demonstrate ‘healthy volunteer bias’—where participants tend to be healthier and more educated than the wider population—and may have lower liability to psychiatric illness, which may result in lower estimates of heritability and genetic correlations.64 The prevalence of self-reported diagnoses of mental illness including depression has been reported to be similar in the Mental Health Questionnaire and representative surveys of the general population of the same age group.26, 65 However, these comparisons have more uncertainty for bipolar disorder and psychotic disorders due to their low prevalence rates and small numbers in the survey data, and it is likely that those with concurrent severe symptoms were less likely to participate.26 The challenges associated with voluntary recruitment for cohort studies including the UK Biobank imply that our findings may be more informative about milder symptoms in the wider population than those with severe mental illness.