@article{discovery1536203, journal = {Biological Psychiatry}, title = {An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype}, year = {2017}, note = {{\copyright} Society of Biological Psychiatry, 2016. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at https://creativecommons.org/licenses/. Access may be initially restricted by the publisher.}, pages = {322--329}, volume = {82}, number = {5}, month = {September}, keywords = {CHARGE consortium, Depressive symptoms, FHIT gene, Genome-wide association study, Major depressive disorder, Psychiatric Genomics Consortium}, issn = {1873-2402}, author = {Direk, N and Williams, S and Smith, JA and Ripke, S and Air, T and Amare, AT and Amin, N and Baune, BT and Bennett, DA and Blackwood, DH and Boomsma, D and Breen, G and Buttensch{\o}n, HN and Byrne, EM and B{\o}rglum, AD and Castelao, E and Cichon, S and Clarke, TK and Cornelis, MC and Dannlowski, U and De Jager, PL and Demirkan, A and Domenici, E and van Duijn, CM and Dunn, EC and Eriksson, JG and Esko, T and Faul, JD and Ferrucci, L and Fornage, M and de Geus, E and Gill, M and Gordon, SD and Grabe, HJ and van Grootheest, G and Hamilton, SP and Hartman, CA and Heath, AC and Hek, K and Hofman, A and Homuth, G and Horn, C and Jan Hottenga, J and Kardia, SL and Kloiber, S and Koenen, K and Kutalik, Z and Ladwig, KH and Lahti, J and Levinson, DF and Lewis, CM and Lewis, G and Li, QS and Llewellyn, DJ and Lucae, S and Lunetta, KL and MacIntyre, DJ and Madden, P and Martin, NG and McIntosh, AM and Metspalu, A and Milaneschi, Y and Montgomery, GW and Mors, O and Mosley, TH and Murabito, JM and M{\"u}ller-Myhsok, B and N{\"o}then, MM and Nyholt, DR and O'Donovan, MC and Penninx, BW and Pergadia, ML and Perlis, R and Potash, JB and Preisig, M and Purcell, SM and Quiroz, JA and R{\"a}ikk{\"o}nen, K and Rice, JP and Rietschel, M and Rivera, M and Schulze, TG and Shi, J and Shyn, S and Sinnamon, GC and Smit, JH and Smoller, JW and Snieder, H and Tanaka, T and Tansey, KE and Teumer, A and Uher, R and Umbricht, D and Van der Auwera, S and Ware, EB and Weir, DR and Weissman, MM and Willemsen, G and Yang, J and Zhao, W and Tiemeier, H and Sullivan, PF}, url = {http://doi.org/10.1016/j.biopsych.2016.11.013}, abstract = {BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 {$\times$} 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 {$\times$} 10(-9)). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.} }