eprintid: 1536203 rev_number: 39 eprint_status: archive userid: 608 dir: disk0/01/53/62/03 datestamp: 2017-01-19 14:54:25 lastmod: 2021-09-20 00:08:51 status_changed: 2017-02-27 14:44:38 type: article metadata_visibility: show creators_name: Direk, N creators_name: Williams, S creators_name: Smith, JA creators_name: Ripke, S creators_name: Air, T creators_name: Amare, AT creators_name: Amin, N creators_name: Baune, BT creators_name: Bennett, DA creators_name: Blackwood, DH creators_name: Boomsma, D creators_name: Breen, G creators_name: Buttenschøn, HN creators_name: Byrne, EM creators_name: Børglum, AD creators_name: Castelao, E creators_name: Cichon, S creators_name: Clarke, TK creators_name: Cornelis, MC creators_name: Dannlowski, U creators_name: De Jager, PL creators_name: Demirkan, A creators_name: Domenici, E creators_name: van Duijn, CM creators_name: Dunn, EC creators_name: Eriksson, JG creators_name: Esko, T creators_name: Faul, JD creators_name: Ferrucci, L creators_name: Fornage, M creators_name: de Geus, E creators_name: Gill, M creators_name: Gordon, SD creators_name: Grabe, HJ creators_name: van Grootheest, G creators_name: Hamilton, SP creators_name: Hartman, CA creators_name: Heath, AC creators_name: Hek, K creators_name: Hofman, A creators_name: Homuth, G creators_name: Horn, C creators_name: Jan Hottenga, J creators_name: Kardia, SL creators_name: Kloiber, S creators_name: Koenen, K creators_name: Kutalik, Z creators_name: Ladwig, KH creators_name: Lahti, J creators_name: Levinson, DF creators_name: Lewis, CM creators_name: Lewis, G creators_name: Li, QS creators_name: Llewellyn, DJ creators_name: Lucae, S creators_name: Lunetta, KL creators_name: MacIntyre, DJ creators_name: Madden, P creators_name: Martin, NG creators_name: McIntosh, AM creators_name: Metspalu, A creators_name: Milaneschi, Y creators_name: Montgomery, GW creators_name: Mors, O creators_name: Mosley, TH creators_name: Murabito, JM creators_name: Müller-Myhsok, B creators_name: Nöthen, MM creators_name: Nyholt, DR creators_name: O'Donovan, MC creators_name: Penninx, BW creators_name: Pergadia, ML creators_name: Perlis, R creators_name: Potash, JB creators_name: Preisig, M creators_name: Purcell, SM creators_name: Quiroz, JA creators_name: Räikkönen, K creators_name: Rice, JP creators_name: Rietschel, M creators_name: Rivera, M creators_name: Schulze, TG creators_name: Shi, J creators_name: Shyn, S creators_name: Sinnamon, GC creators_name: Smit, JH creators_name: Smoller, JW creators_name: Snieder, H creators_name: Tanaka, T creators_name: Tansey, KE creators_name: Teumer, A creators_name: Uher, R creators_name: Umbricht, D creators_name: Van der Auwera, S creators_name: Ware, EB creators_name: Weir, DR creators_name: Weissman, MM creators_name: Willemsen, G creators_name: Yang, J creators_name: Zhao, W creators_name: Tiemeier, H creators_name: Sullivan, PF title: An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D79 keywords: CHARGE consortium, Depressive symptoms, FHIT gene, Genome-wide association study, Major depressive disorder, Psychiatric Genomics Consortium note: © 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. 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 × 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 × 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. date: 2017-09 date_type: published official_url: http://doi.org/10.1016/j.biopsych.2016.11.013 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1200868 doi: 10.1016/j.biopsych.2016.11.013 pii: S0006-3223(16)33068-2 lyricists_name: Lewis, Glyn lyricists_id: GHLEW69 actors_name: Lewis, Glyn actors_id: GHLEW69 actors_role: owner full_text_status: public publication: Biological Psychiatry volume: 82 number: 5 pagerange: 322-329 event_location: United States issn: 1873-2402 citation: Direk, N; Williams, S; Smith, JA; Ripke, S; Air, T; Amare, AT; Amin, N; ... Sullivan, PF; + view all <#> Direk, N; Williams, S; Smith, JA; Ripke, S; Air, T; Amare, AT; Amin, N; Baune, BT; Bennett, DA; Blackwood, DH; Boomsma, D; Breen, G; Buttenschøn, HN; Byrne, EM; Børglum, AD; Castelao, E; Cichon, S; Clarke, TK; Cornelis, MC; Dannlowski, U; De Jager, PL; Demirkan, A; Domenici, E; van Duijn, CM; Dunn, EC; Eriksson, JG; Esko, T; Faul, JD; Ferrucci, L; Fornage, M; de Geus, E; Gill, M; Gordon, SD; Grabe, HJ; van Grootheest, G; Hamilton, SP; Hartman, CA; Heath, AC; Hek, K; Hofman, A; Homuth, G; Horn, C; Jan Hottenga, J; Kardia, SL; Kloiber, S; Koenen, K; Kutalik, Z; Ladwig, KH; Lahti, J; Levinson, DF; Lewis, CM; Lewis, G; Li, QS; Llewellyn, DJ; Lucae, S; Lunetta, KL; MacIntyre, DJ; Madden, P; Martin, NG; McIntosh, AM; Metspalu, A; Milaneschi, Y; Montgomery, GW; Mors, O; Mosley, TH; Murabito, JM; Müller-Myhsok, B; Nöthen, MM; Nyholt, DR; O'Donovan, MC; Penninx, BW; Pergadia, ML; Perlis, R; Potash, JB; Preisig, M; Purcell, SM; Quiroz, JA; Räikkönen, K; Rice, JP; Rietschel, M; Rivera, M; Schulze, TG; Shi, J; Shyn, S; Sinnamon, GC; Smit, JH; Smoller, JW; Snieder, H; Tanaka, T; Tansey, KE; Teumer, A; Uher, R; Umbricht, D; Van der Auwera, S; Ware, EB; Weir, DR; Weissman, MM; Willemsen, G; Yang, J; Zhao, W; Tiemeier, H; Sullivan, PF; - view fewer <#> (2017) An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. Biological Psychiatry , 82 (5) pp. 322-329. 10.1016/j.biopsych.2016.11.013 <https://doi.org/10.1016/j.biopsych.2016.11.013>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1536203/1/Lewis_Direk%202017.pdf