Estimating genetic and environmental sources of variance for depression
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder that is now the leading cause of worldwide disability in terms of years lived with disability. In the majority of Western countries, the lifetime prevalence of MDD typically varies between 8% and 12%. There are consistently established relationships with female gender, alcohol abuse, diabetes, and poor social relationships. The high prevalence and disability associated with MDD make research aimed at understanding its aetiology and developing effective treatments a priority. MDD aggregates within families and the heritability of MDD has been estimated as 37% (SE 5%) in a meta-analysis of twin studies and 32% (SE 9%) using genomic similarity among unrelated individuals. Given the genetic contribution to MDD, genetic studies are a potential means of understanding its aetiology as well as identifying new drug targets. Despite this substantial genetic contribution to its aetiology, candidate gene and genome-wide association studies, including a mega-analysis of more than 20,000 individuals with 9240 cases and 9519 controls in the discovery sample, have failed to identify significantly associated specific genetic variants. Nonetheless, genome-wide association and related studies have shown that MDD is a genetically complex disorder where risk is proposed to result from the cumulative effects of many low-penetrance genetic variants. Increasingly it is also recognised that a diagnosis of MDD may group together individuals who suffer from causally distinct conditions. Some studies indicate that the heritability estimates of MDD differ by sex with female MDD showing higher heritability than male MDD suggesting that the genetic causes may be somewhat distinct. Further, it has been suggested that both age of onset and single versus recurrent episode illness course may have somewhat differing genetic aetiologies. These findings highlight the substantial heterogeneity of MDD, which may further impede the search for genetic causes. There is therefore an urgent need to increase sample sizes and to refine and stratify the phenotype to reduce heterogeneity of phenotypic measurements, and measurement error of MDD with the aim of identifying more genetically homogenous targets for better powered association studies. Pedigree-based genetic studies are an efficient means for dissecting trait heterogeneity because they are able to capture all additive heritability whilst matching for key confounds present in studies of unaffected subjects.
Major depressive disorder, Heritability, Genetic studies, Phenotype heterogeneity, Genome-wide association
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