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Reviewing the genetics of heterogeneity in depression: operationalizations, manifestations and etiologies.

Abstract：

:With progress in genome-wide association studies of depression, from identifying zero hits in ~16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, understanding the genetic architecture of this debilitating condition no longer appears to be an impossible task. The pressing question now is whether recently discovered variants describe the etiology of a single disease entity. There are a myriad of ways to measure and operationalize depression severity, and major depressive disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders-5 can manifest in more than 10 000 ways based on symptom profiles alone. Variations in developmental timing, comorbidity and environmental contexts across individuals and samples further add to the heterogeneity. With big data increasingly enabling genomic discovery in psychiatry, it is more timely than ever to explicitly disentangle genetic contributions to what is likely 'depressions' rather than depression. Here, we introduce three sources of heterogeneity: operationalization, manifestation and etiology. We review recent efforts to identify depression subtypes using clinical and data-driven approaches, examine differences in genetic architecture of depression across contexts, and argue that heterogeneity in operationalizations of depression is likely a considerable source of inconsistency. Finally, we offer recommendations and considerations for the field going forward.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Cai N,Choi KW,Fried EI

doi

10.1093/hmg/ddaa115

subject

Has Abstract

pub_date

2020-09-30 00:00:00

pages

R10-R18

issue

R1

eissn

0964-6906

issn

1460-2083

pii

5860824

journal_volume

29

pub_type

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