Genetics of age-at-onset in major depression

Abstract

Major depression (MD) is a complex, heterogeneous neuropsychiatric disorder. An early age at onset of major depression (AAO-MD) has been associated with more severe illness, psychosis, and suicidality. However, not much is known about what contributes to individual variation in this important clinical characteristic. This study sought to investigate the genetic components underlying AAO-MD. To investigate the genetics of AAO-MD, we conducted a genome-wide association meta-analysis of AAO-MD based on self-reported age of symptoms onset and self-reported age at first diagnosis from the UK Biobank cohort (total N = 94,154). We examined the genetic relationship between AAO-MD and five other psychiatric disorders. Polygenic risk scores were derived to examine their association with five psychiatric outcomes and AAO-MD in independent sub-samples. We found a small but significant SNP-heritability (~6%) for the AAO-MD phenotype. No SNP or gene reached SNP or gene-level significance. We found evidence that AAO-MD has genetic overlap with MD risk ([Formula: see text] = -0.49). Similarly, we found shared genetic risks between AAO-MD and autism-spectrum disorder, schizophrenia, bipolar disorder, and anorexia nervosa ([Formula: see text] range: -0.3 to -0.5). Polygenic risk scores for AAO-MD were associated with MD, schizophrenia, and bipolar disorder, and AAO-MD was in turn associated with polygenic risk scores derived from these disorders. Overall, our results indicate that AAO-MD is heritable, and there is an inverse genetic relationship between AAO-MD and both major depression and other psychiatric disorders, meaning that SNPs associated with earlier age at onset tend to increase the risk for psychiatric disorders. These findings suggest that the genetics of AAO-MD contribute to the shared genetic architecture observed between psychiatric disorders.

Fig. 1. Phenotypic definitions in UK Biobank.

This figure displays the data sources used for each definition, and for what purpose the definition was derived. The two MD definitions are marked with green box color. Data sources and definitions for the exclusion criteria, self-reported lithium/antipsychotics prescriptions, probable depression, and probable bipolar disorder type I and II are marked with gray box color.

Fig. 2. Inverse relationship between AAO-MD and psychiatric disorders.

A Genetic correlations ($r_g$) estimated using High-Definition Likelihood between summary statistics from the meta-analyzed genome-wide association analysis on age at symptoms/diagnosis of major depression and psychiatric traits. The x-axis displays the $r_g$ estimate with error bars displaying the 95% confidence interval. The y-axis displays the psychiatric trait with which the genetic correlation was calculated. B The association between a polygenic risk score derived from genome-wide association analysis from AAO-MD and psychiatric disorders. The y-axis displays the odds ratios of psychiatric disorders per standard deviation decrease in PRS_AAO-MD. The x-axis displays the psychiatric disorder. Error bars display the 95% confidence intervals. The odds ratio estimate is displayed with and without adjustment for MDD-PRS. C The mean PRS for major depression, schizophrenia, and bipolar disorder, stratified by age at symptoms decile. The x-axis displays each decile for age at symptoms. The y-axis displays the mean PRS for each disorder within a decile. Error bars display 95% confidence interval of the mean PRS in each decile.