MDD is defined descriptively without reference to any underlying biology, biomarker or pathophysiology.76,77 Genetic epidemiological studies have suggested that subtypes of MDD might be more familial or have higher heritability (for example, recurrent MDD,10 recurrent early-onset MDD11 and clinically ascertained MDD12). It is possible that well-powered genetic studies of these less common and arguably more heritable forms of MDD would have greater success. However, a sizable fraction of our cases were from hospital sources and our analyses of recurrent MDD and recurrent early-onset MDD were unrevealing, although these observations are qualified by the smaller sample sizes. The selection of a phenotype for genetic studies presents a dilemma for MDD researchers: larger samples which are more representative of the population can be achieved for broadly defined MDD, whereas restricted phenotypes may be more familial but are more difficult to recruit in large numbers from the population. Some other forms of MDD can only be defined using methods that are difficult to operationalize in large samples (for example, extensive clinical interviews, biological assays like repeated hormone measures or brain imaging).
