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Genetic heterogeneity in self-reported depressive symptoms identified through genetic analyses of the PHQ-9

Published online by Cambridge University Press:  18 September 2019

Jackson G. Thorp Open the ORCID record for Jackson G. Thorp [Opens in a new window] ,
Andries T. Marees ,
Jue-Sheng Ong ,
Jiyuan An ,
Stuart MacGregor  and
Eske M. Derks
Jackson G. Thorp*
Affiliation:
Translational Neurogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Andries T. Marees
Affiliation:
Translational Neurogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Jue-Sheng Ong
Affiliation:
Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Jiyuan An
Affiliation:
Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Stuart MacGregor
Affiliation:
Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Eske M. Derks
Affiliation:
Translational Neurogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
*
Author for correspondence: Jackson G. Thorp, E-mail: Jackson.Thorp@qimrberghofer.edu.au and Eske M. Derks, E-mail: Eske.Derks@qimrberghofer.edu.au
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Abstract

Background

Depression is a clinically heterogeneous disorder. Previous large-scale genetic studies of depression have explored genetic risk factors of depression case–control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity.

Methods

We analyse data from 148 752 subjects of white British ancestry in the UK Biobank who completed nine items of a self-rated measure of current depressive symptoms: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD Score Regression was used to calculate SNP-based heritability (h2SNP) and genetic correlations (rg) across symptoms and to investigate genetic correlations with 25 external phenotypes. Genomic structural equation modelling was used to test the genetic factor structure across the nine symptoms.

Results

We identified nine genome-wide significant genomic loci (8 novel), with no overlap in loci across symptoms. h2SNP ranged from 6% (concentration problems) to 9% (appetite changes). Genetic correlations ranged from 0.54 to 0.96 (all p < 1.39 × 10−3) with 30 of 36 correlations being significantly smaller than one. A two-factor model provided the best fit to the genetic covariance matrix, with factors representing ‘psychological’ and ‘somatic’ symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms.

Conclusions

Patterns of SNP associations and genetic correlations differ across the nine symptoms, suggesting that current depressive symptoms are genetically heterogeneous. Our study highlights the value of symptom-level analyses in understanding the genetic architecture of a psychiatric trait. Future studies should investigate whether genetic heterogeneity is recapitulated in clinical symptoms of major depression.

Keywords

Depressiondepressive symptomsgenetic heterogeneityGWASPHQ-9
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 14 , October 2020 , pp. 2385 - 2396
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Copyright
Copyright © Cambridge University Press 2019

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References

American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). Arlington, VA: American Psychiatric Publishing.Google Scholar
Beard, C, Hsu, KJ, Rifkin, LS, Busch, AB and Björgvinsson, T (2016) Validation of the PHQ-9 in a psychiatric sample. Journal of Affective Disorders 193, 267–273.CrossRefGoogle Scholar
Bulik-Sullivan, BK, Finucane, HK, Anttila, V, Gusev, A, Day, FR, Loh, P-R, Reprogen, C, Psychiatric Genomics C, Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control C, Duncan, L, Perry, JRB, Patterson, N, Robinson, EB, Daly, MJ, Price, AL and Neale, BM (2015 a) An atlas of genetic correlations across human diseases and traits. Nature Genetics 47, 1236.CrossRefGoogle ScholarPubMed
Bulik-Sullivan, BK, Loh, P-R, Finucane, HK, Ripke, S, Yang, J, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Patterson, N, Daly, MJ, Price, AL and Neale, BM (2015 b) LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nature Genetics 47, 291.CrossRefGoogle ScholarPubMed
Bycroft, C, Freeman, C, Petkova, D, Band, G, Elliott, LT, Sharp, K, Motyer, A, Vukcevic, D, Delaneau, O, O'connell, J, Cortes, A, Welsh, S, Young, A, Effingham, M, Mcvean, G, Leslie, S, Allen, N, Donnelly, P and Marchini, J (2018) The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209.CrossRefGoogle ScholarPubMed
Cai, N, Bigdeli, TB, Kretzschmar, W, Li, Y, Liang, J, Song, L, Hu, J, Li, Q, Jin, W and Hu, Z (2015) Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523, 588.Google Scholar
Christian, O, Stefan, MG, Brenda, WP, Carmine, MP, Amit, E, Maurizio, F, David, CM and Alan, FS (2016) Major depressive disorder. Nature Reviews Disease Primers 2.Google Scholar
Direk, N, Williams, S, Smith, JA, Ripke, S, Air, T, Amare, AT, Amin, N, Baune, BT, Bennett, DA, Blackwood, DHR, Boomsma, D, Breen, G, Buttenschøn, HN, Byrne, EM, Børglum, AD, Castelao, E, Cichon, S, Clarke, T-K, Cornelis, MC, Dannlowski, U, De Jager, PL, Demirkan, A, Domenici, E, Van Duijn, CM, Dunn, EC, Eriksson, JG, Esko, T, Faul, J. D, Ferrucci, L, Fornage, M, De Geus, E, Gill, M, Gordon, SD, Grabe, H. J, Van Grootheest, G, Hamilton, SP, Hartman, CA, Heath, AC, Hek, K, Hofman, A, Homuth, G, Horn, C, Jan Hottenga, J, Kardia, SLR, Kloiber, S, Koenen, K, Kutalik, Z, Ladwig, K-H, 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 J, M, Müller-Myhsok, B, Nöthen, MM, Nyholt, DR, O'donovan, MC, Penninx, BW, Pergadia, ML, Perlis, R, Potash, JB, Preisig, M, Purcell S, M, 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 and Sullivan, PF (2017) An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype. Biological Psychiatry 82, 322–329.CrossRefGoogle ScholarPubMed
Elhai, JD, Contractor, AA, Tamburrino, M, Fine, TH, Prescott, MR, Shirley, E, Chan, PK, Slembarski, R, Liberzon, I, Galea, S and Calabrese, JR (2012) The factor structure of major depression symptoms: a test of four competing models using the Patient Health Questionnaire-9. Psychiatry Research 199, 169–173.CrossRefGoogle ScholarPubMed
Fried, EI and Nesse, RM (2015) Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. Journal of Affective Disorders 172, 96–102.CrossRefGoogle Scholar
Fromer, M, Roussos, P, Sieberts, SK, Johnson, JS, Kavanagh, DH, Perumal, TM, Ruderfer, DM, Oh, EC, Topol, A, Shah, HR, Klei, LL, Kramer, R, Pinto, D, Gümüş, ZH, Cicek, AE, Dang, KK, Browne, A, Lu, C, Xie, L, Readhead, B, Stahl, EA, Xiao, J, Parvizi, M, Hamamsy, T, Fullard, JF, Wang, Y-C, Mahajan, MC, Derry, JMJ, Dudley, JT, Hemby, SE, Logsdon, BA, Talbot, K, Raj, T, Bennett, DA, De Jager, PL, Zhu, J, Zhang, B, Sullivan, PF, Chess, A, Purcell, SM, Shinobu, LA, Mangravite, LM, Toyoshiba, H, Gur, RE, Hahn, C-G, Lewis, DA, Haroutunian, V, Peters, MA, Lipska, BK, Buxbaum, JD, Schadt, EE, Hirai, K, Roeder, K, Brennand, KJ, Katsanis, N, Domenici, E, Devlin, B and Sklar, P (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience 19, 1442.CrossRefGoogle ScholarPubMed
Gottlieb, DJ, Hek, K, Chen, TH, Watson, NF, Eiriksdottir, G, Byrne, EM, Cornelis, M, Warby, SC, Bandinelli, S, Cherkas, L, Evans, DS, Grabe, HJ, Lahti, J, Li, M, Lehtimaki, T, Lumley, T, Marciante, KD, Perusse, L, Psaty, BM, Robbins, J, Tranah, GJ, Vink, JM, Wilk, JB, Stafford, JM, Bellis, C, Biffar, R, Bouchard, C, Cade, B, Curhan, GC, Eriksson, JG, Ewert, R, Ferrucci, L, Fulop, T, Gehrman, PR, Goodloe, R, Harris, TB, Heath, AC, Hernandez, D, Hofman, A, Hottenga, JJ, Hunter, DJ, Jensen, MK, Johnson, AD, Kahonen, M, Kao, L, Kraft, P, Larkin, EK, Lauderdale, DS, Luik, AI, Medici, M, Montgomery, GW, Palotie, A, Patel, SR, Pistis, G, Porcu, E, Quaye, L, Raitakari, O, Redline, S, Rimm, EB, Rotter, JI, Smith, AV, Spector, TD, Teumer, A, Uitterlinden, AG, Vohl, MC, Widen, E, Willemsen, G, Young, T, Zhang, X, Liu, Y, Blangero, J, Boomsma, DI, Gudnason, V, Hu, F, Mangino, M, Martin, NG, O'connor, GT, Stone, KL, Tanaka, T, Viikari, J, Gharib, SA, Punjabi, NM, Raikkonen, K, Volzke, H, Mignot, E and Tiemeier, H (2015) Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Molecular Psychiatry 20, 1232–1239.CrossRefGoogle ScholarPubMed
Grotzinger, AD, Rhemtulla, M, De Vlaming, R, Ritchie, SJ, Mallard, TT, Hill, WD, Ip, HF, Marioni, RE, Mcintosh, AM, Deary, IJ, Koellinger, PD, Harden, KP, Nivard, MG and Tucker-Drob, EM (2019) Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits. Nature Human Behaviour 3, 513–525.CrossRefGoogle ScholarPubMed
Hall, LS, Adams, MJ, Arnau-Soler, A, Clarke, T-K, Howard, DM, Zeng, Y, Davies, G, Hagenaars, SP, Maria Fernandez-Pujals, A, Gibson, J, Wigmore, EM, Boutin, TS, Hayward, C, Scotland, G, Major Depressive Disorder Working Group of the Psychiatric Genomics C, Porteous, DJ, Deary, IJ, Thomson, PA, Haley, CS and Mcintosh, AM (2018) Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank. Translational Psychiatry 8, 9.CrossRefGoogle ScholarPubMed
Hek, K, Demirkan, A, Lahti, J, Terracciano, A, Teumer, A, Cornelis, MC, Amin, N, Bakshis, E, Baumert, J, Ding, J, Liu, Y, Marciante, K, Meirelles, O, Nalls, MA, Sun, YV, Vogelzangs, N, Yu, L, Bandinelli, S, Benjamin, EJ, Bennett, DA, Boomsma, D, Cannas, A, Coker, LH, De Geus, E, De Jager, PL, Diez-Roux, AV, Purcell, S, Hu, FB, Rimma, EB, Hunter, DJ, Jensen, MK, Curhan, G, Rice, K, Penman, AD, Rotter, JI, Sotoodehnia, N, Emeny, R, Eriksson, JG, Evans, DA, Ferrucci, L, Fornage, M, Gudnason, V, Hofman, A, Illig, T, Kardia, S, Kelly-Hayes, M, Koenen, K, Kraft, P, Kuningas, M, Massaro, JM, Melzer, D, Mulas, A, Mulder, CL, Murray, A, Oostra, BA, Palotie, A, Penninx, B, Petersmann, A, Pilling, LC, Psaty, B, Rawal, R, Reiman, EM, Schulz, A, Shulman, JM, Singleton, AB, Smith, AV, Sutin, AR, Uitterlinden, AG, Volzke, H, Widen, E, Yaffe, K, Zonderman, AB, Cucca, F, Harris, T, Ladwig, KH, Llewellyn, DJ, Raikkonen, K, Tanaka, T, Van Duijn, CM, Grabe, HJ, Launer, LJ, Lunetta, KL, Mosley, TH Jr, Newman, AB, Tiemeier, H and Murabito, J (2013) A genome-wide association study of depressive symptoms. Biological Psychiatry 73, 667–678.CrossRefGoogle ScholarPubMed
Hettema, JM, Neale, MC, Myers, JM, Prescott, CA and Kendler, KS (2006) A population-based twin study of the relationship between neuroticism and internalizing disorders. American Journal of Psychiatry 163, 857–864.CrossRefGoogle ScholarPubMed
Higgins, JP and Thompson, SG (2002) Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 21, 1539–1558.CrossRefGoogle ScholarPubMed
Howard, DM, Adams, MJ, Shirali, M, Clarke, T-K, Marioni, RE, Davies, G, Coleman, JRI, Alloza, C, Shen, X, Barbu, MC, Wigmore, EM, Gibson, J, Hagenaars, SP, Lewis, CM, Ward, J, Smith, DJ, Sullivan, PF, Haley, CS, Breen, G, Deary, IJ and Mcintosh, AM (2018) Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nature Communications 9, 1470.CrossRefGoogle ScholarPubMed
Howard, DM, Adams, MJ, Clarke, T-K, Hafferty, JD, Gibson, J, Shirali, M, Coleman, JRI, Hagenaars, SP, Ward, J, Wigmore, EM, Alloza, C, Shen, X, Barbu, MC, Xu, EY, Whalley, HC, Marioni, RE, Porteous, DJ, Davies, G, Deary, IJ, Hemani, G, Berger, K, Teismann, H, Rawal, R, Arolt, V, Baune, BT, Dannlowski, U, Domschke, K, Tian, C, Hinds, DA, Trzaskowski, M, Byrne, EM, Ripke, S, Smith, DJ, Sullivan, PF, Wray, NR, Breen, G, Lewis, CM, Mcintosh, AM, 23andme Research Team and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2019) Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience 22, 343–352.CrossRefGoogle ScholarPubMed
Hyde, CL, Nagle, MW, Tian, C, Chen, X, Paciga, SA, Wendland, JR, Tung, JY, Hinds, DA, Perlis, RH and Winslow, AR (2016) Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nature Genetics 48, 1031.CrossRefGoogle ScholarPubMed
Jang, KL, Livesley, WJ, Taylor, S, Stein, MB and Moon, EC (2004) Heritability of individual depressive symptoms. Journal of Affective Disorders 80, 125–133.CrossRefGoogle ScholarPubMed
Jones, SE, Tyrrell, J, Wood, AR, Beaumont, RN, Ruth, KS, Tuke, MA, Yaghootkar, H, Hu, Y, Teder-Laving, M, Hayward, C, Roenneberg, T, Wilson, JF, Del Greco, F, Hicks, AA, Shin, C, Yun, C-H, Lee, SK, Metspalu, A, Byrne, EM, Gehrman, PR, Tiemeier, H, Allebrandt, KV, Freathy, RM, Murray, A, Hinds, DA, Frayling, TM and Weedon, MN (2016) Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. PLOS Genetics 12, e1006125.CrossRefGoogle Scholar
Kendler, KS, Aggen, SH and Neale, MC (2013) Evidence for multiple genetic factors underlying dsm-iv criteria for major depression. JAMA Psychiatry 70, 599–607.CrossRefGoogle ScholarPubMed
Kline, RB (2005) Principles and Practice of Structural Equation Modeling, 2nd ed. New York, NY, US: Guilford Press.Google Scholar
Kohli, MA, Lucae, S, Saemann, PG, Schmidt, MV, Demirkan, A, Hek, K, Czamara, D, Alexander, M, Salyakina, D, Ripke, S, Hoehn, D, Specht, M, Menke, A, Hennings, J, Heck, A, Wolf, C, Ising, M, Schreiber, S, Czisch, M, Müller, MB, Uhr, M, Bettecken, T, Becker, A, Schramm, J, Rietschel, M, Maier, W, Bradley, B, Ressler, KJ, Nöthen, MM, Cichon, S, Craig, IW, Breen, G, Lewis, CM, Hofman, A, Tiemeier, H, Van duijn, CM, Holsboer, F, Müller-Myhsok, B and Binder, EB (2011) The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron 70, 252–265.CrossRefGoogle ScholarPubMed
Krause, JS, Bombardier, C and Carter, RE (2008) Assessment of depressive symptoms during inpatient rehabilitation for spinal cord injury: is there an underlying somatic factor when using the PHQ? Rehabilitation Psychology 53, 513.CrossRefGoogle Scholar
Krause, JS, Reed, KS and Mcardle, JJ (2010) Factor structure and predictive validity of somatic and nonsomatic symptoms from the Patient Health Questionnaire-9: a longitudinal study after spinal cord injury. Archives of Physical Medicine and Rehabilitation 91, 1218–1224.CrossRefGoogle ScholarPubMed
Kroenke, K, Spitzer, RL and Williams, JBW (2001 a) The PHQ-9. Journal of General Internal Medicine 16, 606–613.CrossRefGoogle ScholarPubMed
Kroenke, K, Spitzer, RL and Williams, JBW (2001 b) The PHQ-9: validity of a brief depression severity measure. Journal of General Internal Medicine 16, 606–613.CrossRefGoogle ScholarPubMed
Lamers, F, Vogelzangs, N, Merikangas, KR, De Jonge, P, Beekman, AT and Penninx, BW (2013) Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Molecular Psychiatry 18, 692–699.CrossRefGoogle ScholarPubMed
Lane, JM, Liang, J, Vlasac, I, Anderson, SG, Bechtold, DA, Bowden, J, Emsley, R, Gill, S, Little, MA, Luik, AI, Loudon, A, Scheer, FAJL, Purcell, SM, Kyle, SD, Lawlor, DA, Zhu, X, Redline, S, Ray, DW, Rutter, MK and Saxena, R (2017) Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nature Genetics 49, 274–281.CrossRefGoogle ScholarPubMed
Lee, SH, Ripke, S, Neale, BM, Faraone, SV, Purcell, SM, Perlis, RH, Mowry, BJ, Thapar, A, Goddard, ME and Witte, JS (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45, 984.Google ScholarPubMed
Levinson, DF, Mostafavi, S, Milaneschi, Y, Rivera, M, Ripke, S, Wray, NR and Sullivan, PF (2014) Genetic studies of major depressive disorder: why are there no genome-wide association study findings and what can we do about it? Biological Psychiatry 76, 510–512.CrossRefGoogle Scholar
Li, X, Luo, Z, Gu, C, Hall, LS, Mcintosh, AM, Zeng, Y, Porteous, DJ, Hayward, C, Li, M, Yao, Y-G, Zhang, C, Luo, X-J and The 23andme Research Team (2018) Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder. Neuropsychopharmacology 43, 2146–2153.CrossRefGoogle ScholarPubMed
Loh, P-R, Tucker, G, Bulik-Sullivan, BK, Vilhjálmsson, BJ, Finucane, HK, Salem, RM, Chasman, DI, Ridker, PM, Neale, BM, Berger, B, Patterson, N and Price, AL (2015) Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nature Genetics 47, 284.CrossRefGoogle ScholarPubMed
Loh, P-R, Kichaev, G, Gazal, S, Schoech, AP and Price, AL (2018) Mixed-model association for biobank-scale datasets. Nature Genetics 50, 906–908.CrossRefGoogle ScholarPubMed
Lonsdale, J, Thomas, J, Salvatore, M, Phillips, R, Lo, E, Shad, S, Hasz, R, Walters, G, Garcia, F, Young, N, Foster, B, Moser, M, Karasik, E, Gillard, B, Ramsey, K, Sullivan, S, Bridge, J, Magazine, H, Syron, J, Fleming, J, Siminoff, L, Traino, H, Mosavel, M, Barker, L, Jewell, S, Rohrer, D, Maxim, D, Filkins, D, Harbach, P, Cortadillo, E, Berghuis, B, Turner, L, Hudson, E, Feenstra, K, Sobin, L, Robb, J, Branton, P, Korzeniewski, G, Shive, C, Tabor, D, Qi, L, Groch, K, Nampally, S, Buia, S, Zimmerman, A, Smith, A, Burges, R, Robinson, K, Valentino, K, Bradbury, D, Cosentino, M, Diaz-Mayoral, N, Kennedy, M, Engel, T, Williams, P, Erickson, K, Ardlie, K, Winckler, W, Getz, G, Deluca, D, Macarthur, D, Kellis, M, Thomson, A, Young, T, Gelfand, E, Donovan, M, Meng, Y, Grant, G, Mash, D, Marcus, Y, Basile, M, Liu, J, Zhu, J, Tu, Z, Cox, NJ, Nicolae, DL, Gamazon, ER, Im, HK, Konkashbaev, A, Pritchard, J, Stevens, M, Flutre, T, Wen, X, Dermitzakis, ET, Lappalainen, T, Guigo, R, Monlong, J, Sammeth, M, Koller, D, Battle, A, Mostafavi, S, Mccarthy, M, Rivas, M, Maller, J, Rusyn, I, Nobel, A, Wright, F, Shabalin, A, Feolo, M, Sharopova, N, Sturcke, A, Paschal, J, Anderson, JM, Wilder, EL, Derr, LK, Green, ED, Struewing, JP, Temple, G, Volpi, S, Boyer, JT, Thomson, EJ, Guyer, MS, Ng, C, Abdallah, A, Colantuoni, D, Insel, TR, Koester, SE, Little, AR, Bender, PK, Lehner, T, Yao, Y, Compton, CC, Vaught, JB, Sawyer, S, Lockhart, NC, Demchok, J and Moore, HF (2013) The Genotype-Tissue Expression (GTEx) project. Nature Genetics 45, 580.CrossRefGoogle Scholar
Motivala, SJ, Sarfatti, A, Olmos, L and Irwin, MR (2005) Inflammatory markers and sleep disturbance in major depression. Psychosomatic Medicine 67, 187–194.CrossRefGoogle ScholarPubMed
Myung, W, Song, J, Lim, S-W, Won, H-H, Kim, S, Lee, Y, Kang, HS, Lee, H, Kim, J-W, Carroll, BJ and Kim, DK (2012) Genetic association study of individual symptoms in depression. Psychiatry Research 198, 400–406.CrossRefGoogle ScholarPubMed
Nagel, M, Jansen, PR, Stringer, S, Watanabe, K, De Leeuw, CA, Bryois, J, Savage, JE, Hammerschlag, AR, Skene, NG, Muñoz-Manchado, AB, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Furlotte, NA, Hinds, DA, Hromatka, BS, Huber, KE, Kleinman, A, Litterman, NK, Mcintyre, MH, Mountain, JL, Noblin, ES, Northover, C a M, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Tung, JY, Vacic, V, Wilson, CH, White, T, Tiemeier, H, Linnarsson, S, Hjerling-Leffler, J, Polderman, TJC, Sullivan, PF, Van Der Sluis, S, Posthuma, D and 23andme Research Team (2018 a) Meta-analysis of genome-wide association studies for neuroticism in 449, 484 individuals identifies novel genetic loci and pathways. Nature Genetics 50, 920–927.CrossRefGoogle ScholarPubMed
Nagel, M, Watanabe, K, Stringer, S, Posthuma, D and Van Der Sluis, S (2018 b) Item-level analyses reveal genetic heterogeneity in neuroticism. Nature Communications 9, 905.CrossRefGoogle ScholarPubMed
Okbay, A, Baselmans, BML, De Neve, JE, Turley, P, Nivard, MG, Fontana, MA, Meddens, SFW, Linnér, RK, Rietveld, CA, Derringer, J, Gratten, J, Lee, JJ, Liu, JZ, De Vlaming, R, Ahluwalia, TS, Buchwald, J, Cavadino, A, Frazier-Wood, AC, Furlotte, NA, Garfield, V, Geisel, MH, Gonzalez, JR, Haitjema, S, Karlsson, R, Van Der Laan, SW, Ladwig, K-H, Lahti, J, Van Der Lee, SJ, Lind, PA, Liu, T, Matteson, L, Mihailov, E, Miller, MB, Minica, CC, Nolte, IM, Mook-Kanamori, D, Van Der Most, PJ, Oldmeadow, C, Qian, Y, Raitakari, O, Rawal, R, Realo, A, Rueedi, R, Schmidt, B, Smith, AV, Stergiakouli, E, Tanaka, T, Taylor, K, Thorleifsson, G, Wedenoja, J, Wellmann, J, Westra, H-J, Willems, SM, Zhao, W, Lifelines Cohort, S, Amin, N, Bakshi, A, Bergmann, S, Bjornsdottir, G, Boyle, PA, Cherney, S, Cox, SR, Davies, G, Davis, OSP, Ding, J, Direk, N, Eibich, P, Emeny, RT, Fatemifar, G, Faul, JD, Ferrucci, L, Forstner, AJ, Gieger, C, Gupta, R, Harris, TB, Harris, JM, Holliday, EG, Hottenga, J-J, De Jager, PL, Kaakinen, MA, Kajantie, E, Karhunen, V, Kolcic, I, Kumari, M, Launer, LJ, Franke, L, Li-Gao, R, Liewald, DC, Koini, M, Loukola, A, Marques-Vidal, P, Montgomery, GW, Mosing, MA, Paternoster, L, Pattie, A, Petrovic, KE, Pulkki-Råback, L, Quaye, L, Räikkönen, K, Rudan, I, Scott, RJ, Smith, JA, Sutin, AR, Trzaskowski, M, Vinkhuyzen, A E, Yu, L, Zabaneh, D, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Boomsma, DI, Snieder, H, Chang, S-C, Cucca, F, Deary, IJ, Van Duijn, CM, Eriksson, JG, Bültmann, U, De Geus, EJC, Groenen, PJF, Gudnason, V, Hansen, T, Hartman, CA, Haworth, CMA, Hayward, C, Heath, AC, Hinds, DA, Hyppönen, E, Iacono, WG, Järvelin, M-R, Jöckel, K-H, Kaprio, J, Kardia, SLR, Keltikangas-Järvinen, L, Kraft, P, Kubzansky, LD, Lehtimäki, T, Magnusson, PKE, Martin, NG, Mcgue, M, Metspalu, A, Mills, M, De Mutsert, R, Oldehinkel, AJ, Pasterkamp, G, Pedersen, NL, Plomin, R, Polasek, O, Power, C, Rich, SS, Rosendaal, FR, Den Ruijter, HM, Schlessinger, D, Schmidt, H, Svento, R, Schmidt, R, Alizadeh, BZ, Sørensen, TIA, Spector, TD, Starr, JM, Stefansson, K, Steptoe, A, Terracciano, A, Thorsteinsdottir, U, hurik, AR, Timpson, NJ, Tiemeier, H, Uitterlinden, AG, Vollenweider, P, Wagner, GG, Weir, DR, Yang, J, Conley, DC, Smith, GD, Hofman, A, Johannesson, M, Laibson, DI, Medland, SE, Meyer, MN, Pickrell, JK, Esko, T, Krueger, RF, Beauchamp, JP, Koellinger, PD, Benjamin, DJ, Bartels, M and Cesarini, D (2016) Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nature Genetics 48, 624.CrossRefGoogle ScholarPubMed
Østergaard, SD, Jensen, SOW and Bech, P (2011) The heterogeneity of the depressive syndrome: when numbers get serious. Acta Psychiatrica Scandinavica 124, 495–496.CrossRefGoogle ScholarPubMed
Petersen, JJ, Paulitsch, MA, Hartig, J, Mergenthal, K, Gerlach, FM and Gensichen, J (2015) Factor structure and measurement invariance of the Patient Health Questionnaire-9 for female and male primary care patients with major depression in Germany. Journal of Affective Disorders 170, 138–142.CrossRefGoogle ScholarPubMed
Power, RA, Tansey, KE, Buttenschøn, HN, Cohen-Woods, S, Bigdeli, T, Hall, LS, Kutalik, Z, Lee, SH, Ripke, S, Steinberg, S, Teumer, A, Viktorin, A, Wray, NR, Arolt, V, Baune, BT, Boomsma, DI, Børglum, AD, Byrne, EM, Castelao, E, Craddock, N, Craig, IW, Dannlowski, U, Deary, IJ, Degenhardt, F, Forstner, AJ, Gordon, SD, Grabe, HJ, Grove, J, Hamilton, SP, Hayward, C, Heath, AC, Hocking, LJ, Homuth, G, Hottenga, JJ, Kloiber, S, Krogh, J, Landén, M, Lang, M, Levinson, DF, Lichtenstein, P, Lucae, S, Macintyre, DJ, Madden, P, Magnusson, PKE, Martin, NG, Mcintosh, AM, Middeldorp, CM, Milaneschi, Y, Montgomery, GW, Mors, O, Müller-Myhsok, B, Nyholt, DR, Oskarsson, H, Owen, MJ, Padmanabhan, S, Penninx, BWJH, Pergadia, ML, Porteous, DJ, Potash, JB, Preisig, M, Rivera, M, Shi, J, Shyn, SI, Sigurdsson, E, Smit, JH, Smith, BH, Stefansson, H, Stefansson, K, Strohmaier, J, Sullivan, PF, Thomson, P, Thorgeirsson, TE, Van Der Auwera, S, Weissman, MM, Converge Consortium CCGC, Breen, G and Lewis, CM (2017) Genome-wide association for major depression through age at onset stratification: major depressive disorder working group of the psychiatric genomics consortium(). Biological Psychiatry 81, 325–335.CrossRefGoogle Scholar
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MAR, Bender, D, Maller, J, Sklar, P, De Bakker, PIW, Daly, MJ and Sham, PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics 81, 559–575.CrossRefGoogle ScholarPubMed
Ripke, S, Sanders, AR, Kendler, KS, Levinson, DF, Sklar, P, Holmans, PA, Lin, D-Y, Duan, J, Ophoff, RA and Andreassen, OA (2011) Genome-wide association study identifies five new schizophrenia loci. Nature Genetics 43, 969.Google Scholar
Ripke, S, Wray, NR, Lewis, CM, Hamilton, SP, Weissman, MM, Breen, G, Byrne, EM, Blackwood, DH, Boomsma, DI, Cichon, S, Heath, AC, Holsboer, F, Lucae, S, Madden, PA, Martin, NG, Mcguffin, P, Muglia, P, Noethen, MM, Penninx, BP, Pergadia, ML, Potash, JB, Rietschel, M, Lin, D, Muller-Myhsok, B, Shi, J, Steinberg, S, Grabe, HJ, Lichtenstein, P, Magnusson, P, Perlis, RH, Preisig, M, Smoller, JW, Stefansson, K, Uher, R, Kutalik, Z, Tansey, KE, Teumer, A, Viktorin, A, Barnes, MR, Bettecken, T, Binder, EB, Breuer, R, Castro, VM, Churchill, SE, Coryell, WH, Craddock, N, Craig, IW, Czamara, D, De Geus, EJ, Degenhardt, F, Farmer, AE, Fava, M, Frank, J, Gainer, VS, Gallagher, PJ, Gordon, SD, Goryachev, S, Gross, M, Guipponi, M, Henders, AK, Herms, S, Hickie, IB, Hoefels, S, Hoogendijk, W, Hottenga, JJ, Iosifescu, DV, Ising, M, Jones, I, Jones, L, Jung-Ying, T, Knowles, JA, Kohane, IS, Kohli, MA, Korszun, A, Landen, M, Lawson, WB, Lewis, G, Macintyre, D, Maier, W, Mattheisen, M, Mcgrath, PJ, Mcintosh, A, Mclean, A, Middeldorp, CM, Middleton, L, Montgomery, GM, Murphy, SN, Nauck, M, Nolen, WA, Nyholt, DR, O'donovan, M, Oskarsson, H, Pedersen, N, Scheftner, WA, Schulz, A, Schulze, TG, Shyn, SI, Sigurdsson, E, Slager, SL, Smit, JH, Stefansson, H, Steffens, M, Thorgeirsson, T, Tozzi, F, Treutlein, J, Uhr, M, Van Den Oord, EJ, Van Grootheest, G, Volzke, H, Weilburg, JB, Willemsen, G, Zitman, FG, Neale, B, Daly, M, Levinson, DF and Sullivan, PF 2013. A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry , 18, 497–511.Google ScholarPubMed
Ripke, S, Neale, BM, Corvin, A, Walters, JT, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA and Huang, H (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421.Google Scholar
Stewart, AL, Hays, RD and Ware, JE Jr (1988) The MOS short-form general health survey. Reliability and validity in a patient population. Medical Care 26, 724–735.CrossRefGoogle Scholar
Sullivan, PF, Neale, MC and Kendler, KS (2000) Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry 157, 1552–1562.CrossRefGoogle ScholarPubMed
Watanabe, K, Taskesen, E, Bochoven, A and Posthuma, D (2017) Functional mapping and annotation of genetic associations with FUMA. Nature Communications 8, 1826.CrossRefGoogle ScholarPubMed
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 and Sullivan, PF (2012) Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Molecular Psychiatry 17, 36–48.CrossRefGoogle ScholarPubMed
Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TMF, Bacanu, S-A, Bækvad-Hansen, M, Beekman, AFT, Bigdeli, TB, Binder, EB, Blackwood, DRH, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JIR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Crowley, CA, Dashti, HS, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Eriksson, N, Escott-Price, V, Kiadeh, FHF, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Giusti-Rodríguez, P, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hannon, E, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Hu, M, Hyde, CL, Ising, M, Jansen, R, Jin, F, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Lane, JM, Li, Y, Li, Y, Lind, PA, Liu, X, Lu, L, 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, Mill, J, 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, Purcell, SM, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Saeed Mirza, S, Saxena, R, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GBC, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Stockmeier, CA, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Tian, C, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van Der Auwera, S, 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, ECJ, Depaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Hinds, DA, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PFA, Magnusson, PK, Martin, NG, Mcintosh, AM, 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, Winslow, AR, Lewis, CM, Levinson, DF, Breen, G, Børglum, AD, Sullivan, PF, Eqtlgen, 23andme and The Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics 50, 668–681.CrossRefGoogle ScholarPubMed
Zhou, W, Nielsen, JB, Fritsche, LG, Dey, R, Gabrielsen, ME, Wolford, BN, Lefaive, J, Vandehaar, P, Gagliano, SA, Gifford, A, Bastarache, LA, Wei, W-Q, Denny, JC, Lin, M, Hveem, K, Kang, HM, Abecasis, GR, Willer, CJ and Lee, S (2018) Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nature Genetics 50, 1335–1341.CrossRefGoogle ScholarPubMed
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