The genetic basis of major depressive disorder.

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.

重度抑郁症（MDD）的基因解析堪称精神遗传学的成功案例之一，全基因组关联研究（GWAS）确定了178个遗传风险位点，并提出了200多个候选基因。然而，GWAS的结果来自对队列的分析，其中大多数病例是通过最简表型分析诊断的，这种方法特异性较低。我回顾的数据表明，MDD存在大量独特的基因成分，最简表型分析策略无法触及，而且通过最简表型分析方法确定的大多数遗传风险位点不太可能是MDD的风险位点。我表明，创造性地利用生物样本库数据、新的归因方法，再结合更多由访谈者诊断的病例，可以确定导致情绪的间歇性严重波动以及对MDD至关重要的植物神经和认知变化的位点。此外，借鉴神经科学和心理学的进展，关于MDD的性质和病因的新理论可以为如何最好地解释和利用基因定位结果提供思路。