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Lancet. 2013 Apr 20;381(9875):1371-9. doi: 10.1016/S0140-6736(12)62129-1. Epub 2013 Feb 28.

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

Collaborators (313)

Smoller JW, Ripke S, Lee PH, Neale B, Nurnberger JI, Santangelo S, Sullivan PF, Perlis RH, Purcell SM, Fanous A, Neale MC, Rietschel M, Schulze TG, Thapar A, Anney R, Buitelaar JK, Farone SV, Hoogendijk WJ, Levinson DF, Lesch KP, Riley B, Schachar R, Sonuga-Barke E, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Arking D, Asherson P, Azevedo MH, Backlund L, Badner JA, Banaschewski T, Barchas JD, Barnes MR, Bass N, Bauer M, Bellivier F, Bergen SE, Berrettini W, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Buccola NG, Bunner WE, Burmeister M, Buxbaum JD, Byerley WF, Sian C, Cantor RM, Chakravarti A, Chambert K, Chicon S, Cloniger CR, Collier DA, Cook E, Coon H, Corvin A, Coryell WH, Craig DW, Craig IW, Curtis D, Czamara D, Daly M, Datta S, Day R, De Geus EJ, Degenhardt F, Devlin B, Srdjan D, Doyle AE, Duan J, Dudbridge F, Edenberg HJ, Elkin A, Etain B, Farmer AE, Ferreira MA, Ferrier IN, Flickinger M, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Friedl M, Frisén L, Gejman PV, Georgieva L, Gershon ES, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Gross M, Grozeva D, Guan W, Gurling H, Gustafsson Ó, Hakonarson H, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hottenga JJ, Hultman CM, Ingason A, Ising M, Jamain S, Jones EG, Jones L, Jones I, Jung-Ying T, Kahler A, Kandaswamy R, Keller MC, Kelsoe JR, Kennedy JL, Kenny E, Kim Y, Kirov GK, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krasucki R, Kuntsi J, Phoenix K, Landén M, Langstrom N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Lencz T, Lesch KP, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin D, Liu C, Lohoff FW, Loo SK, Lucae S, MacIntyre D, Madden PA, Magnusson P, Mahon PB, Maier W, Malhotra AK, Mattheisen M, Matthews K, Mattingsdal M, McCarroll S, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McClean AW, McMahon FJ, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Middeldorp CM, Middleton L, Vihra M, Mitchell PB, Montgomery GW, Moran J, Morken G, Morris DW, Moskvina V, Mowry BJ, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Myers RM, Nelson SF, Nievergelt CM, Nikolovq I, Nimgaonkar V, Nolen WA, Nöthen MM, Nwulia EA, Nyholt DR, O'Donovan MC, O'Dushlaine C, Oades RD, Olincy A, Olsen L, Ophoff RA, Osby U, Óskarsson H, Owen MJ, Palotie A, Pato MT, Pato CN, Penninx BP, Pergadia ML, Petursson H, Pickard BS, Pimm J, Piven J, Porgeirsson P, Posthuma D, Potash JB, Propping J, Puri V, Quested D, Quinn EM, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Rice J, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Schalling M, Schatzberg AF, Schftner WA, Schellenberg G, Schofield PR, Schork NJ, Schumacher J, Schwarz MM, Scolnick E, Scott LJ, Shi J, Shillling PD, Shyn SI, Sigurdsson E, Silverman JM, Sklar P, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke E, St Clair D, State M, Stefansson K, Stefansson H, Steffans M, Steinberg S, Steinhausen HC, Strauss J, Strohmaier J, Stroup TS, Sutcliffe J, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Vieland V, Vincent JB, Visscher PM, Watson SJ, Weissman MM, Werge T, Wienker TF, Willemsen G, Williamson R, Witt SH, Wray NR, Wright A, Xu W, Young AH, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Craddock N, Kendler K.

Erratum in

  • Lancet. 2013 Apr 20;381(9875):1360.

Abstract

BACKGROUND:

Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

METHODS:

We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.

FINDINGS:

SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.

INTERPRETATION:

Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

FUNDING:

National Institute of Mental Health.

PMID:
23453885
PMCID:
PMC3714010
DOI:
10.1016/S0140-6736(12)62129-1
[Indexed for MEDLINE]
Free PMC Article
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