Identifying social or environmental modifiers of genetic risks is a critical next step to understand depression etiology. Acknowledgments The research was supported by National Institutes of Health/National Institute of Mental Health (NIH/NIMH) (MH092707-01). The authors thank Middeldorp for the excellent collaboration and providing the risk estimates from the previously published study. The authors are also indebted to the participants in the Nurses’ Health Study for their outstanding commitment and cooperation. Appendix 1 Nested Genetic Case–Control Studies in NHS Participants

Inhibitors,research,lifescience,medical for the current analyses were from four independent GWAS nested in the NHS initially designed to study Inhibitors,research,lifescience,medical outcomes of breast cancer (BrCa, N = 2280), coronary heart disease (CHD, N = 1135), type 2 diabetes (T2D, N = 3084), and kidney stone (KS, N = 490) disease. Both cases and controls in each original GWAS were included for analysis. Briefly, for the NHS BrCa study, cases and controls were limited to postmenopausal

women. Controls were matched with cases by age and postmenopausal hormone use at blood draw. For the NHS CHD study, controls were randomly selected from the subcohort who provided blood samples and did not experience CHD with two controls Inhibitors,research,lifescience,medical for each case, matched with cases by age, smoking, and month of blood draw. For the NHS T2D study, controls who were defined to be those free of diabetes at the time the case was reported were matched on year of birth, month of blood collection, and fasting status. For the NHS KS study, participants with a history of kidney stones were matched to randomly selected controls identified in two cycles from those with no history of cancer (cycles 1 and 2) or cardiovascular disease (cycle 1) who met age eligibility Inhibitors,research,lifescience,medical requirements (cycle 1: <66; cycle 2: <76). A total

of 2280 women from the NHS BrCa substudy, 1135 women from the CHD substudy, 3084 women from the T2D, Inhibitors,research,lifescience,medical and 490 women in the KS substudy, all unrelated and genetically defined whites who had nonmissing phenotype and covariate data, were included in this study (total N = 6989). Appendix 2 Construction of a 14-Year Long-Term Average Depression Measure The Nurses’ Health Study (NHS) began collecting depression-related measures starting in 1992. Information on clinical and subclinical levels of depression has been protein inhibitor assessed with a variety of measures across seven subsequent interview waves. For example, information on clinician-diagnosed Batimastat depression has been assessed every 2 years since 2000, and information on antidepressant use has been collected every 2 years since 1996. Questionnaire-based measures with relevant symptom items were also administered, including the SF-36, Center for Epidemiologic Studies Depression Scale—10 items (CESD-10), life orientation test, and geriatric depression scale—15 items (glucose metabolism GDS-15). These have been assessed either once or at multiple points (Table S1).