A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Shen X., Howard DM., Adams MJ., Hill WD., Clarke T-K., Adams MJ., Clarke T-K., McIntosh AM., Deary IJ., Wray NR., Ripke S., Mattheisen M., Trzaskowski M., Byrne EM., Abdellaoui A., Agerbo E., Air TM., Andlauer TFM., Bacanu S-A., Bækvad-Hansen M., Beekman ATF., Bigdeli TB., Binder EB., Bryois J., Buttenschøn HN., Bybjerg-Grauholm J., Cai N., Castelao E., Christensen JH., Coleman JRI., Colodro-Conde L., Couvy-Duchesne B., Craddock N., Crawford GE., Davies G., Degenhardt F., Derks EM., Direk N., Dolan CV., Dunn EC., Eley TC., Escott-Price V., Kiadeh FFH., Finucane HK., Foo JC., Forstner AJ., Frank J., Gaspar HA., Gill M., Goes FS., Gordon SD., Grove J., Hall LS., Hansen CS., Hansen TF., Herms S., Hickie IB., Hoffmann P., Homuth G., Horn C., Hottenga J-J., Hougaard DM., Howard DM., Ising M., Jansen R., Jones I., Jones LA., Jorgenson E., Knowles JA., Kohane IS., Kraft J., Kretzschmar WW., Kutalik Z., Li Y., Lind PA., MacIntyre DJ., MacKinnon DF., Maier RM., Maier W., Marchini J., Mbarek H., McGrath P., McGuffin P., Medland SE., Mehta D., Middeldorp CM., Mihailov E., Milaneschi Y., Milani L., Mondimore FM., Montgomery GW., Mostafavi S., Mullins N., Nauck M., Ng B., Nivard MG., Nyholt DR., O’Reilly PF., Oskarsson H., Owen MJ., Painter JN., Pedersen CB., Pedersen MG., Peterson RE., Pettersson E., Peyrot WJ., Pistis G., Posthuma D., Quiroz JA., Qvist P., Rice JP., Riley BP., Rivera M., Mirza SS., Schoevers R., Schulte EC., Shen L., Shi J., Shyn SI., Sigurdsson E., Sinnamon GCB., Smit JH., Smith DJ., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey KE., Teismann H., Teumer A., Thompson W., Thomson PA., Thorgeirsson TE., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden AG., Umbricht D., Auwera SVD., van Hemert AM., Viktorin A., Visscher PM., Wang Y., Webb BT., Weinsheimer SM., Wellmann J., Willemsen G., Witt SH., Wu Y., Xi HS., Yang J., Zhang F., Arolt V., Baune BT., Berger K., Boomsma DI., Cichon S., Dannlowski U., de Geus EJC., DePaulo JR., Domenici E., Domschke K., Esko T., Grabe HJ., Hamilton SP., Hayward C., Heath AC., Kendler KS., Kloiber S., Lewis G., Li QS., Lucae S., Madden PAF., Magnusson PK., Martin NG., Metspalu A., Mors O., Mortensen PB., Müller-Myhsok B., Nordentoft M., Nöthen MM., O’Donovan MC., Paciga SA., Pedersen NL., Penninx BWJH., Perlis RH., Porteous DJ., Potash JB., Preisig M., Rietschel M., Schaefer C., Schulze TG., Smoller JW., Stefansson K., Tiemeier H., Uher R., Völzke H., Weissman MM., Werge T., Lewis CM., Levinson DF., Breen G., Børglum AD., Sullivan PF., Deary IJ., Whalley HC., McIntosh AM.
AbstractDepression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10−14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.