Abstract
The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.
Highlights
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder that is the leading cause of worldwide disability in terms of years lived with disability [1]
Reweighting the sample based on population frequencies of age, sex, and Scottish Index of Multiple Deprivation 2009 (SIMD), this is equivalent to an estimated population prevalence of 12.2% (CI 11.4%–13.1%)
We compared this regression of the reported data to the uniform distribution of age of onset expected if onset was reported uniformly by participants after age 11 (See S1 Fig)
Summary
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder that is the leading cause of worldwide disability in terms of years lived with disability [1]. 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 [10] and genome-wide association studies [11], including a mega-analysis of more than 20,000 individuals with 9240 cases and 9519 controls in the discovery sample [12], have failed to identify significantly associated specific genetic variants [13]. Genome-wide association and related studies have shown that MDD is a genetically complex disorder [14] where risk is proposed to result from the cumulative effects of many low-penetrance genetic variants [9, 12]
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