Mitchell BL, Thorp JG, Wu Y, et al. - According to this case-control polygenic risk score analysis, increasing sample sizes, independent of phenotyping depth, may be most useful for assessing depression risk. Like the Australian Genetics of Depression Study, the next generation of genome-wide association studies should have high sample numbers and rigorous phenotyping to capture genetic risk factors for major depressive disorder (MDD) that aren't detected by conventional definitions of depression.

• There were 12,106 patients with MDD (71% female; mean age, 42.3 years; range, 18-88 years) and 12,621 control individuals with no history of psychiatric illnesses (55% female; mean age, 60.9 years; range, 43-87 years).

• The PRS effect size was proportional to the discovery sample size, with the largest study having the largest effect size with the odds ratio for MDD per SD of PRS and the PRS derived from ICD-10 codes documented in hospitalization records in a population health cohort having the lowest odds ratio.

• When differences in sample size were taken into account, the PRS from a genome-wide association study of patients meeting diagnostic criteria for MDD and control participants was the best estimator of MDD, but not in those with self-reported depression, and there were associations with higher odds ratios with childhood adverse experiences and measures of somatic distress.