ABSTRACTBackgroundMajor 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.MethodsUsing 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∼3,000-47,000). To compare genetic architecture 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 or traits.ResultsMD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (age at onset, suicidality, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtypes 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 features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (−0.09) was found in those with non-atypical symptoms. Novel genomic loci with subtype-specific effects were identified.ConclusionsThese 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.
Genetic heterogeneity and subtypes of major depression
