Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden.
Mol Psychiatry. 2022 Mar;27(3):1667-1675. doi: 10.1038/s41380-021-01413-6. Epub 2022 Jan 8.
Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment, and postpartum depression; N ~ 3000-47000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders/traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.
重度抑郁症（MD）是一种异质性疾病；然而，遗传因素在多大程度上区分 MD 患者亚组（遗传异质性）仍不确定。本研究旨在为 MD 的遗传异质性提供证据。作者使用英国生物库队列，在八个比较组内定义了 16 种 MD 亚型（植物神经症状、症状严重程度、共患焦虑障碍、发病年龄、复发、自杀意念、功能障碍和产后抑郁；N~3000-47000）。为了比较这些亚型的遗传成分，对每个亚型进行了特定的全基因组关联研究，以估计 SNP 遗传力，以及亚型内比较和与其他相关障碍/特征的遗传相关性。研究结果表明，MD 亚型在 SNP 遗传力和亚型内比较以及与其他相关障碍/特征的遗传相关性方面存在差异。三种亚型比较（植物神经症状、发病年龄和功能障碍）在 SNP 遗传力方面存在显著差异；而亚型内比较的遗传相关性范围从 0.55 到 0.86，表明 MD 亚型的遗传特征仅部分共享。此外，更具临床挑战性的亚型，如发病早、复发、自杀、功能障碍更严重，与其他精神障碍的遗传相关性更强。具有非典型特征的 MD 与 BMI 呈正遗传相关性（+0.40），而无非典型特征的 MD 则呈负遗传相关性（-0.09）。还确定了具有亚型特异性效应的新基因组位点。这些结果为 MD 内遗传异质性提供了迄今为止最全面的证据，并表明通过研究具有部分不同病因的亚型，可以有效地降低 MD 的表型复杂性。
