Applying polygenic risk scores to postpartum depression
- 657 Downloads
The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p = 0.02. The proportion of variance (R 2) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p = 0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R 2 > 1.1 %, p < 0.008), where the majority of cases met criteria for MDD. The genetic overlap between BPD and MDD was not significant in larger Australian and Dutch MDD case/control cohorts after excluding PPD cases (R 2 = 0.06 %, p = 0.08), despite the larger MDD group affording more power. Our results suggest an empirical genetic evidence for a more important shared genetic etiology between BPD and PPD than between BPD and MDD.
KeywordsDepression Postpartum Bipolar
Australia: This research was directly supported by the Australian Research Council (FT0991360) and the Australian National Health and Medical Research Council (613608). Support was received by the National Institutes of Health: DA12854, AA13320, AA13321, DA019951. We acknowledge Professor Matthew Brown for genotyping undertaken at the University of Queensland Centre for Clinical Genomics, housed at UQ’s Diamantina Institute. A portion of the statistical analyses were carried out on the QIMR GenEpi Cluster, which is financially supported by contributions from grants from the Australian National Health and Medical Research Council (389892; 496682; 496688; 496739; 613672). We thank the ATR twins for their continued participation. We also thank Dixie Statham, Bronwyn Morris and Megan Ferguson for coordinating the data collection for the twins; David Smyth, Olivia Zheng and Harry Beeby for data management; Lisa Bowdler, Steven Crooks (DNA processing) and Sarah Medland, Dale Nyholt and Scott Gordon (imputation and genotyping QC).
NTR/NESDA: The Netherlands Study of Depression and Anxiety (NESDA) and The Netherlands Twin Register (NTR) were funded by The Netherlands Organization for Scientific Research (MagW/ZonMW grants 904-61-090, 985-10-002,904-61-193,480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program grant 10-000-1002); the Center for Medical Systems Biology (CMSB2; NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University EMGO+ Institute for Health and Care Research and the Neuroscience Campus Amsterdam, NBIC/BioAssist/RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community’s Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413) and the European Science Council (ERC, 230374). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan and 1RC2 MH089995 PI Hudziak) and as part of the American Recovery and Reinvestment Act of 2009. We acknowledge Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06) and the Avera Institute, Sioux Falls, South Dakota (USA).
ALSPAC: A grant from the Wellcome Trust (WT088806) provided funds for the ALSPAC genome-wide data used in this study and for G.M’s salary at the time analyses with these data were undertaken. The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. H.M.S. was funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic and life course epidemiology (WT099871MA). H.M.S, D.A.L, and D.M.E work in a unit that receives research funds from the MRC. The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses
STR: The Swedish Twin Registry is supported by the Swedish Department of Higher Education, the European Commission European Network for Genetic and Genomic Epidemiology (ENGAGE: 7th Framework Program (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 and GenomEUtwin: 5th Framework program “Quality of Life and Management of the Living Resources” Grant QLG2-CT-2002-01254); the NIH (DK U01-066134); the Swedish Research Council (M-2005–1112 and 2009–2298); the Swedish Foundation for Strategic Research (ICA08-0047); the Jan Wallander and Tom Hedelius Foundation; and the Swedish Council for Working Life and Social Research.
Conflict of interest
The authors declare no conflict of interest.
- Boomsma DI, Willemsen G, Sullivan PF, Heutink P, Meijer P, Sondervan D, Kluft C, Smit G, Nolen WA, Zitman FG, Smit JH, Hoogendijk WJ, van Dyck R, de Geus EJ, Penninx BW (2008) Genome-wide association of major depression: description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects. Eur J Hum Genet 16:335–342PubMedCrossRefGoogle Scholar
- Cross-Disorder Group of the Psychiatric Genomics, Lee C, Ripke SH, Neale S, Faraone BM, Purcell SV, Perlis SM, Mowry RH, Thapar BJ, Goddard A, Witte ME, Absher JS, Agartz D, Akil I, Amin H, Andreassen F, Anjorin OA, Anney A, Anttila R, Arking V, Asherson DE, Azevedo P, Backlund MH, Badner L, Bailey JA, Banaschewski AJ, Barchas T, Barnes JD, Barrett MR, Bass TB, Battaglia N, Bauer A, Bayes M, Bellivier M, Berrettini SE, Betancur W, Bettecken C, Biederman T, Binder J, Black EB, Blackwood DW, Bloss DH, Boehnke CS, Boomsma M, Breen DI, Breuer G, Bruggeman R, Cormican R, Buccola P, Buitelaar NG, Bunney JK, Buxbaum WE, Byerley JD, Byrne WF, Caesar EM, Cahn S, Cantor W, Casas RM, Chakravarti M, Chambert A, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, de Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–94PubMedCrossRefGoogle Scholar
- Fraser A, Macdonald-Wallis C, Tilling K, Boyd A, Golding J, Davey Smith G, Henderson J, Macleod J, Molloy L, Ness A, Ring S, Nelson SM, Awlor DA (2013) Cohort profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort. Int J Epidemiol 42:97–110PubMedCentralPubMedCrossRefGoogle Scholar
- Lee SH, Decandia TR, Ripke S, Yang J, Schizophrenia Psychiatric Genome-Wide Association Study, C., International Schizophrenia, C., Molecular Genetics of Schizophrenia, C, Sullivan PF, Goddard ME, Keller MC, Visscher PM, Wray NR (2012a) Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 44:247PubMedCentralPubMedCrossRefGoogle Scholar
- Lewis CM, Ng MY, Butler AW, Cohen-Woods S, Uher R, Pirlo K, Weale ME, Schosser A, Paredes UM, Rivera M, Craddock N, Owen MJ, Jones L, Jones I, Korszun A, Aitchison KJ, Shi J, Quinn JP, Mackenzie A, Vollenweider P, Waeber G, Heath S, Lathrop M, Muglia P, Barnes MR, Whittaker JC, Tozzi F, Holsboer F, Preisig M, Farmer AE, Breen G, Craig IW, Mcguffin P (2010) Genome-wide association study of major recurrent depression in the U.K. population. Am J Psychiatry 167:949–957PubMedCrossRefGoogle Scholar
- Lubke GH, Hottenga JJ, Walters R, Laurin C, de Geus EJ, Willemsen G, Smit JH, Middeldorp CM, Penninx BW, Vink JM, Boomsma DI (2012) Estimating the genetic variance of major depressive disorder due to all single nucleotide polymorphisms. Biol Psychiatry 72:707–709PubMedCentralPubMedCrossRefGoogle Scholar
- Magnusson PK, Almqvist C, Rahman I, Ganna A, Viktorin A, Walum H, Halldner L, Lundstrom S, Ullen F, Langstrom N, Larsson H, Nyman A, Gumpert CH, Rastam M, Anckarsater H, Cnattingius S, Johannesson M, Ingelsson E, Klareskog L, de Faire U, Pedersen NL, Lichtenstein P (2013) The Swedish twin registry: establishment of a biobank and other recent developments. Twin Res Hum Genet 16:317–329PubMedCrossRefGoogle Scholar
- Mahon PB, Payne JL, Mackinnon DF, Mondimore FM, Goes FS, Schweizer B, Jancic D, Coryell WH, Holmans PA, Shi JX, Knowles JA, Scheftner WA, Weissman MM, Levinson DF, Depaulo JR, Zandi PP, Potash JB, D, N. G. I. B. and CONSORTIUM B (2009) Genome-wide linkage and follow-up association study of postpartum mood symptoms. Am J Psychiatry 166: 1229–1237Google Scholar
- Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18:497–511Google Scholar
- Meltzer-Brody S, Boschloo L, Jones I, Sullivan PF, Penninx BW (2013) The EPDS-Lifetime: assessment of lifetime prevalence and risk factors for perinatal depression in a large cohort of depressed women. Arch Women's Ment Health 16:465–473Google Scholar
- Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ, Antoniades A, Domenici E, Perry J, Rothen S, Vandeleur CL, Mooser V, Waeber G, Vollenweider P, Preisig M, Lucae S, Muller-Myhsok B, Holsboer F, Middleton LT, Roses AD (2010) Genome-wide association study of recurrent major depressive disorder in two European case–control cohorts. Mol Psychiatry 15:589–601PubMedCrossRefGoogle Scholar
- Penninx BW, Beekman AT, Smit JH, Zitman FG, Nolen WA, Spinhoven P, Cuijpers P, de Jong PJ, van Marwijk HW, Assendelft WJ, van der Meer K, Verhaak P, Wensing M, de Graaf R, Hoogendijk WJ, Ormel J, van Dyck R (2008) The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. Int J Methods Psychiatr Res 17:121–140PubMedCrossRefGoogle Scholar
- Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, Kim Y, Lee SH, Magnusson PK, Sanchez N, Stahl EA, Williams S, Wray NR, Xia K, Bettella F, Borglum AD, Bulik-Sullivan BK, Cormican P, Craddock N, de Leeuw C, Durmishi N, Gill M, Golimbet V, Hamshere ML, Holmans P, Hougaard DM, Kendler KS, Lin K, Morris DW, Mors O, Mortensen PB, Neale BM, O’Neill FA, Owen MJ, Milovancevic MP, Posthuma D, Powell J, Richards AL, Riley BP, Ruderfer D, Rujescu D, Sigurdsson E, Silagadze T, Smit AB, Stefansson H, Steinberg S, Suvisaari J, Tosato S, Verhage M, Walters JT, Multicenter Genetic Studies of Schizophrenia, Multicenter Genetic Studies of Schizophrenia, C, Levinson DF, Gejman PV, Kendler KS, Laurent C, Mowry BJ, O’Donovan MC, Owen MJ, Pulver AE, Riley BP, Schwab SG, Wildenauer DB, Dudbridge F, Holmans P, Shi J, Albus M, Alexander M, Campion D, Cohen D, Dikeos D, Duan J, Eichhammer P, Godard S, Hansen M, Lerer FB, Liang KY, Maier W, Mallet J, Nertney DA, Nestadt G, Norton N, O’Neill FA, Papadimitriou GN, Ribble R, Sanders AR, Silverman JM, Walsh D, Williams NM, Wormley B, Psychosis Endophenotypes International, C, Arranz MJ, Bakker S, Bender S, Bramon E, Collier D, Crespo-Facorro B et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45:1150–1159PubMedCrossRefGoogle Scholar
- Shi J, Potash JB, Knowles JA, Weissman MM, Coryell W, Scheftner WA, Lawson WB, Depaulo JR Jr, Gejman PV, Sanders AR, Johnson JK, Adams P, Chaudhury S, Jancic D, Evgrafov O, Zvinyatskovskiy A, Ertman N, Gladis M, Neimanas K, Goodell M, Hale N, Ney N, Verma R, Mirel D, Holmans P, Levinson DF (2011) Genome-wide association study of recurrent early-onset major depressive disorder. Mol Psychiatry 16:193–201PubMedCrossRefGoogle Scholar
- Shyn SI, Shi J, Kraft JB, Potash JB, Knowles JA, Weissman MM, Garriock HA, Yokoyama JS, Mcgrath PJ, Peters EJ, Scheftner WA, Coryell W, Lawson WB, Jancic D, Gejman PV, Sanders AR, Holmans P, Slager SL, Levinson DF, Hamilton SP (2011) Novel loci for major depression identified by genome-wide association study of sequenced treatment alternatives to relieve depression and meta-analysis of three studies. Mol Psychiatry 16:202–215PubMedCentralPubMedCrossRefGoogle Scholar
- Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N, Edenberg HJ, Nurnberger JI Jr, Rietschel M, Blackwood D, Corvin A, Flickinger M, Guan W, Mattingsdal M, Mcquillin A, Kwan P, Wienker TF, Daly M, Dudbridge F, Holmans PA, Lin D, Burmeister M, Greenwood TA, Hamshere ML, Muglia P, Smith EN, Zandi PP, Nievergelt CM, Mckinney R, Shilling PD, Schork NJ, Bloss CS, Foroud T, Koller DL, Gershon ES, Liu C, Badner JA, Scheftner WA, Lawson WB, Nwulia EA, Hipolito M, Coryell W, Rice J, Byerley W, Mcmahon FJ, Schulze TG, Berrettini W, Lohoff FW, Potash JB, Mahon PB, Mcinnis MG, Zollner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Breuer R, Meier S, Strohmaier J, Witt SH, Tozzi F, Farmer A, Mcguffin P, Strauss J, Xu W, Kennedy JL, Vincent JB, Matthews K, Day R, Ferreira MA, O’Dushlaine C, Perlis R, Raychaudhuri S, Ruderfer D, Hyoun PL, Smoller JW, Li J, Absher D, Thompson RC, Meng FG, Schatzberg AF, Bunney WE, Barchas JD, Jones EG, Watson SJ, Myers RM, Akil H, Boehnke M, Chambert K, Moran J, Scolnick E, Djurovic S, Melle I, Morken G, Gill M, Morris D, Quinn E, Muhleisen TW, Degenhardt FA, Mattheisen M et al (2011) Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 43:977–983PubMedCentralCrossRefGoogle Scholar
- Sullivan PF, de Geus EJ, Willemsen G, James MR, Smit JH, Zandbelt T, Arolt V, Baune BT, Blackwood D, Cichon S, Coventry WL, Domschke K, Farmer A, Fava M, Gordon SD, He Q, Heath AC, Heutink P, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hu Y, Kohli M, Lin D, Lucae S, Macintyre DJ, Maier W, Mcghee KA, Mcguffin P, Montgomery GW, Muir WJ, Nolen WA, Nothen MM, Perlis RH, Pirlo K, Posthuma D, Rietschel M, Rizzu P, Schosser A, Smit AB, Smoller JW, Tzeng JY, van Dyck R, Verhage M, Zitman FG, Martin NG, Wray NR, Boomsma DI, Penninx BW (2009) Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry 14:359–375PubMedCentralPubMedCrossRefGoogle Scholar
- Wittchen HU, Robins LN, Cottler LB, Sartorius N, Burke JD, Regier D (1991) Cross-cultural feasibility, reliability and sources of variance of the Composite International Diagnostic Interview (CIDI). The Multicentre WHO/ADAMHA Field Trials. Br J Psychiatry 159(645–53):658Google Scholar
- Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, Ripke S, Macintyre DJ, Mcghee KA, Maclean AW, Smit JH, Hottenga JJ, Willemsen G, Middeldorp CM, de Geus EJ, Lewis CM, Mcguffin P, Hickie IB, van den Oord EJ, Liu JZ, Macgregor S, Mcevoy BP, Byrne EM, Medland SE, Statham DJ, Henders AK, Heath AC, Montgomery GW, Martin NG, Boomsma DI, Madden PA, Sullivan PF (2012) Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry 17:36–48PubMedCentralPubMedCrossRefGoogle Scholar