The genetic basis of major depressive disorder

Abstract

The genetic dissection of major depressive disorder (MDD) ranks as one of the success stories of psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 genetic risk loci and proposing more than 200 candidate genes. However, the GWAS results derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating that there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci. I show that inventive uses of biobank data, novel imputation methods, combined with more interviewer diagnosed cases, can identify loci that contribute to the episodic severe shifts of mood, and neurovegetative and cognitive changes that are central to MDD. Furthermore, new theories about the nature and causes of MDD, drawing upon advances in neuroscience and psychology, can provide handles on how best to interpret and exploit genetic mapping results.

Fig. 1. The relationship between sample size and the number of genome-wide significant loci.

The relationship between the number of cases of MDD (plotted on the horizontal axis) to the number of genome-wide significant loci discovered (plotted on the vertical axis). Each dot represents the findings from a GWAS study.

Fig. 2. GWAS hits from minimal phenotyping definition of MDD in UKBiobank are not specific to MDD.

The figure shows 27 loci, listed on the vertical axis, that are significantly associated with a minimal-phenotyping definition of MDD in UKBiobank (GPpsy). The odds ratios (OR) are shown on the horizontal axis for the minimal phenotype, for a DSM-diagnosis of MDD and for the personality trait, neuroticism. The latter is a quantitative phenotype, so to allow comparison with the binary traits, the effect size estimates from the regression (beta values) have been converted into odds ratios. Data are from [25].