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GWAS Goes Bigger: Large Sample Sizes Uncover New Risk Loci, Additional Overlap in Schizophrenia and Bipolar Disorder

20 September 2011. The results of the largest GWAS on schizophrenia and bipolar disorder to date were published online September 18 in Nature Genetics. From the Psychiatric Genome-Wide Consortium (PGC), each study reaches combined sample sizes in the tens of thousands, and delivers multiple genome-wide significant hits to the complicated realm of psychiatric genetics.

The schizophrenia study replicates two known risk loci and uncovers five new ones, including an intriguing hit involving the microRNA (miRNA) MIR137, a player in neural development. The new bipolar disorder GWAS replicates previous findings of CACNA1C, and reveals a new risk locus on chromosome 11 near ODZ4, a gene that encodes an extracellular matrix protein involved in signal transduction.

In addition to these main results, both studies also analyzed combined samples of individuals diagnosed with schizophrenia and those with bipolar disorder, and provide further evidence for the view that there is significant overlap in the genetic bases of these illnesses (Craddock and Owen, 2010; SRF related news story).

Pumping up the volume
In the summer of 2009, three GWAS of schizophrenia and bipolar disorder, including the largest such study conducted up to that time, were published simultaneously in Nature to great fanfare (International Schizophrenia Consortium et al., 2009; Shi et al., 2009; Stefansson et al., 2009; see also SRF related news story). A meta-analysis of all three datasets (Shi et al., 2009) in one of the papers provided converging evidence of associations (albeit none with genomewide significance) between schizophrenia and gene variations in the major histocompatibility complex (MHC), which had previously been seen in linkage (Schwab et al., 2002) and candidate-gene (Lewis et al., 2003) studies. Otherwise, the work revealed numerous associations with weak effect and few replications, pointing toward a polygenic etiology for schizophrenia and bipolar disorder—an overall finding that scientists involved in the studies predicted would be corroborated and strengthened with larger sample sizes.

The schizophrenia GWAS published this week (Schizophrenia Psychiatric Genome-Wide Association Study Consortium, 2011) provides one of the first tests of this prediction. Members of the PGC completed a mega-analysis of raw data from 17 previous GWAS, including 13 from the International Schizophrenia Consortium and SGENE Consortium, for a combined total sample size of 29,839 individuals. In this first stage, 136 associations reached genomewide significance, most of which were in a 5.5 Mb region of the MHC.

The group also found significant signals at two previously reported sites—TCF4 on chromosome 18 and near NRGN (albeit a different NRGN variant than had been seen previously) on chromosome 11, and two entirely new loci at 10q24.33 (in NT5C2) and 8q21.3 (near MMP16).

Eighty-one SNPs surpassing a significance criterion (P <2 x 10-5) were examined in a second replication stage utilizing an independent combined sample of 21,397 cases and 8,442 controls, and the same direction of effect was observed for 49 of 52 SNPs identified in stage 1. Finally, the stage 1 and 2 samples were combined for a dataset totaling 51,695 individuals, comprising 17,836 cases and 33,859 controls. In this analysis, seven loci yielded signals with genomewide significance. Two of these loci—a stretch at 6p21.32-p22.1 in TRIM26 and at 18q21.2, where two separate SNPs were found in TCF4 and near CCDC68—had been previously identified, but five—at 1p21.3, 2q32.3, 8p23.2, 8q21.3, and 10q24.32-q24.33—are new.

The newly identified SNP on chromosome 1 (rs1625579), which falls within an intron of the primary transcript of MIR137, showed the strongest association of all in the combined sample (P = 1.62 x 10-11). This miRNA is known to regulate neural development and adult neurogenesis via many gene targets (e.g., Smrt et al., 2010), and it is among the miRNAs implicated in recent “genetic imaging” studies of schizophrenia (Potkin et al., 2010). Interestingly, in stage 1 of the study, SNPs were also found in numerous MIR137 gene targets, which corroborates the idea that misregulation of MIR137 represents a new etiologic mechanism in schizophrenia.

Three loci that surfaced during stage 1—ANK3, CACN1AC, and ITIH3-ITIH4—have been associated with bipolar disorder. To ascertain whether these genes confer risk for both schizophrenia and bipolar disorder, the authors analyzed a combined sample of 16,374 patients with schizophrenia, schizoaffective disorder, or bipolar disorder and 14,044 controls. All three regions achieved genomewide significance in this analysis, lending further support to the idea that there is shared genetic risk among these disorders.

A new SNP, and more overlap
In another three-stage study by PGC members on bipolar disorder (Psychiatric GWAS Consortium Bipolar Working Group, 2011), 34 SNPs identified in a discovery phase were narrowed to 18 in a replication study utilizing independent cases. Then, combining the discovery and replication samples for a total of 11,974 cases and 51,792 controls, they turned up significantly associated SNPs in the CACN1AC region of chromosome 12 (rs476913) and in an intron of ODZ4, a human homologue of the Drosophila pair-rule gene ten-m. ODZ4 encodes extracellular matrix glycoproteins known as tenascins that are involved in signal transduction.

A parallel study examined a combined sample of schizophrenia and bipolar disorder patients independent of that discussed above, which replicated that study’s association of CACN1AC and also found a significant signal at a multigenic locus in the NEK4-ITIH1-ITIH3-ITIH4 region of chromosome 3 with both schizophrenia and bipolar disorder. That this mixing together of bipolar and schizophrenia cases in both studies results in clear hits argues that signals can be discerned even when dealing with highly heterogeneous psychiatric disorders—as long as the sample size is large enough.

Overall, the multiple hits of small effect found in these studies fit with a polygenic model of schizophrenia and bipolar disorder. Though even larger GWAS will be needed to discover a fuller complement of risk variants, chasing down the biology of these variants will be essential to understanding their contributions to psychiatric disease.—Pete Farley.

References:
The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, Lin DY, Duan J, Ophoff RA, Andreassen OA, Scolnick E, Cichon S, St Clair D, Corvin A, Gurling H, Werge T, Rujescu D, Blackwood DH, Pato CN, Malhotra AK, Purcell S, Dudbridge F, Neale BM, Rossin L, Visscher PM, Posthuma D, Ruderfer DM, Fanous A, Stefansson H, Steinberg S, Mowry BJ, Golimbet V, De Hert M, Jönsson EG, Bitter I, Pietiläinen OP, Collier DA, Tosato S, Agartz I, Albus M, Alexander M, Amdur RL, Amin F, Bass N, Bergen SE, Black DW, Børglum AD, Brown MA, Bruggeman R, Buccola NG, Byerley WF, Cahn W, Cantor RM, Carr VJ, Catts SV, Choudhury K, Cloninger CR, Cormican P, Craddock N, Danoy PA, Datta S, de Haan L, Demontis D, Dikeos D, Djurovic S, Donnelly P, Donohoe G, Duong L, Dwyer S, Fink-Jensen A, Freedman R, Freimer NB, Friedl M, Georgieva L, Giegling I, Gill M, Glenthøj B, Godard S, Hamshere M, Hansen M, Hansen T, Hartmann AM, Henskens FA, Hougaard DM, Hultman CM, Ingason A, Jablensky AV, Jakobsen KD, Jay M, Jürgens G, Kahn RS, Keller MC, Kenis G, Kenny E, Kim Y, Kirov GK, Konnerth H, Konte B, Krabbendam L, Krasucki R, Lasseter VK, Laurent C, Lawrence J, Lencz T, Lerer FB, Liang KY, Lichtenstein P, Lieberman JA, Linszen DH, Lönnqvist J, Loughland CM, Maclean AW, Maher BS, Maier W, Mallet J, Malloy P, Mattheisen M, Mattingsdal M, McGhee KA, McGrath JJ, McIntosh A, McLean DE, McQuillin A, Melle I, Michie PT, Milanova V, Morris DW, Mors O, Mortensen PB, Moskvina V, Muglia P, Myin-Germeys I, Nertney DA, Nestadt G, Nielsen J, Nikolov I, Nordentoft M, Norton N, Nöthen MM, O'Dushlaine CT, Olincy A, Olsen L, O'Neill FA, Orntoft TF, Owen MJ, Pantelis C, Papadimitriou G, Pato MT, Peltonen L, Petursson H, Pickard B, Pimm J, Pulver AE, Puri V, Quested D, Quinn EM, Rasmussen HB, Réthelyi JM, Ribble R, Rietschel M, Riley BP, Ruggeri M, Schall U, Schulze TG, Schwab SG, Scott RJ, Shi J, Sigurdsson E, Silverman JM, Spencer CC, Stefansson K, Strange A, Strengman E, Stroup TS, Suvisaari J, Terenius L, Thirumalai S, Thygesen JH, Timm S, Toncheva D, van den Oord E, van Os J, van Winkel R, Veldink J, Walsh D, Wang AG, Wiersma D, Wildenauer DB, Williams HJ, Williams NM, Wormley B, Zammit S, Sullivan PF, O'Donovan MC, Daly MJ, Gejman PV. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011 Sep 18. Abstract

Psychiatric GWAS Consortium Bipolar Disorder Working Group, Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N, Edenberg HJ, Nurnberger JI Jr, Rietschel M, Blackwood D, Corvin A, Flickinger M, Guan W, Mattingsdal M, McQuillin A, Kwan P, Wienker TF, Daly M, Dudbridge F, Holmans PA, Lin D, Burmeister M, Greenwood TA, Hamshere ML, Muglia P, Smith EN, Zandi PP, Nievergelt CM, McKinney R, Shilling PD, Schork NJ, Bloss CS, Foroud T, Koller DL, Gershon ES, Liu C, Badner JA, Scheftner WA, Lawson WB, Nwulia EA, Hipolito M, Coryell W, Rice J, Byerley W, McMahon FJ, Schulze TG, Berrettini W, Lohoff FW, Potash JB, Mahon PB, McInnis MG, Zöllner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Breuer R, Meier S, Strohmaier J, Witt SH, Tozzi F, Farmer A, McGuffin P, Strauss J, Xu W, Kennedy JL, Vincent JB, Matthews K, Day R, Ferreira MA, O'Dushlaine C, Perlis R, Raychaudhuri S, Ruderfer D, Hyoun PL, Smoller JW, Li J, Absher D, Thompson RC, Meng FG, Schatzberg AF, Bunney WE, Barchas JD, Jones EG, Watson SJ, Myers RM, Akil H, Boehnke M, Chambert K, Moran J, Scolnick E, Djurovic S, Melle I, Morken G, Gill M, Morris D, Quinn E, Mühleisen TW, Degenhardt FA, Mattheisen M, Schumacher J, Maier W, Steffens M, Propping P, Nöthen MM, Anjorin A, Bass N, Gurling H, Kandaswamy R, Lawrence J, McGhee K, McIntosh A, McLean AW, Muir WJ, Pickard BS, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Williamson R, Young AH, Ferrier IN, Stefansson K, Stefansson H, Thornorgeirsson T, Steinberg S, Gustafsson O, Bergen SE, Nimgaonkar V, Hultman C, Landén M, Lichtenstein P, Sullivan P, Schalling M, Osby U, Backlund L, Frisén L, Langstrom N, Jamain S, Leboyer M, Etain B, Bellivier F, Petursson H, Sigur Sson E, Müller-Mysok B, Lucae S, Schwarz M, Schofield PR, Martin N, Montgomery GW, Lathrop M, Oskarsson H, Bauer M, Wright A, Mitchell PB, Hautzinger M, Reif A, Kelsoe JR, Purcell SM. Large-scale genome-wide association analysis of bipolar disorder reveals a new susceptibility locus near ODZ4. Nat Genet. 2011 Sep 18. Abstract

 
Comments on News and Primary Papers
Comment by:  David J. Porteous, SRF Advisor
Submitted 21 September 2011 Posted 21 September 2011

Consorting with GWAS for schizophrenia and bipolar disorder: same message, (some) different genes
On 18 September 2011, Nature Genetics published the results from the Psychiatric Genetics Consortium of two separate, large-scale GWAS analyses, for schizophrenia (Ripke et al., 2011) and for bipolar disorder (Sklar et al., 2011), and a joint analysis of both. By combining forces across several consortia who have previously published separately, we should now have some clarity and definitive answers.

For schizophrenia, the Stage 1 GWAS discovery data came from 9,394 cases and 12,462 controls from 17 studies, imputing 1,252,901 SNPs. The Stage 2 replication sample comprised 8,442 cases and 21,397 controls. Of the 136 SNPs which reached genomewide significance in Stage 1, 129 (95 percent) mapped to the MHC locus, long known to be associated with risk of schizophrenia. Of the remaining seven SNPs, five mapped to previously identified loci. In total, just 10 loci met or...  Read more


View all comments by David J. Porteous

Comment by:  Patrick Sullivan, SRF Advisor
Submitted 26 September 2011 Posted 26 September 2011
  I recommend the Primary Papers

The two papers appearing online in Nature Genetics last Sunday are truly important additions to our increasing knowledge base for these disorders. The core analyses have been presented multiple times at international meetings in the past two years.

Since then, the available sample sizes for both schizophrenia and bipolar disorder have grown considerably. If the recently published data are any guide, the next round of analyses should be particularly revealing.

The PGC results and almost all of the data that were used in these reports are available by application to the controlled-access repository.

Please see the references for views of this area that contrast with those of Professor Porteous.

References:

Sullivan P. Don't give up on GWAS. Molecular Psychiatry. 2011 Aug 9. Abstract

Kim Y, Zerwas S, Trace SE, Sullivan PF. Schizophrenia genetics: where next? Schizophr Bull. 2011;37:456-63. Abstract

View all comments by Patrick Sullivan


Comment by:  Edward Scolnick
Submitted 28 September 2011 Posted 29 September 2011
  I recommend the Primary Papers

It is clear in human genetics that common variants and rare variants have frequently been detected in the same genes. Numerous examples exist in many diseases. The bashing of GWAS in schizophrenia and bipolar illness indicates, by those who make such comments, a lack of understanding of human genetics and where the field is. When these studies were initiated five years ago, next-generation sequencing was not available. Large samples of populations or trios or quartets did not exist. The international consortia have worked to collect such samples that are available for GWAS now, as well as for detailed sequencing studies. Before these studies began there was virtually nothing known about the etiology of schizophrenia and bipolar illness. The DISC1 gene translocation in the famous family was an important observation in that family. But almost a decade later there is still no convincing data that variants in Disc1 or many of its interacting proteins are involved in the pathogenesis of human schizophrenia or major mental illness.

Sequencing studies touted to be the Occam's...  Read more


View all comments by Edward Scolnick

Comment by:  Nick CraddockMichael O'Donovan (SRF Advisor)
Submitted 11 October 2011 Posted 11 October 2011

At the start of the millennium, only two molecular genetic findings could be said with a fair amount of confidence to be etiologically relevant to schizophrenia and bipolar disorder. The first of these was that deletions of chromosome 22q11 that are known to cause velo-cardio-facial syndrome also confer a substantial increase in risk of psychosis. The second was the discovery by David St Clair, Douglas Blackwood, and colleagues (St Clair et al., 1990) of a balanced translocation involving chromosomes 1 and 11 that co-segregates with a range of psychiatric phenotypes in a single large family, was clearly relevant to the etiology of illness in that family (Blackwood et al., 2001). The latter finding has led to the conjecture, based upon a translocation breakpoint analysis reported by Kirsty Millar, David Porteous, and colleagues (Millar et al., 2000), that elevated risk in that family is conferred by altered function of a gene eponymously...  Read more


View all comments by Nick Craddock
View all comments by Michael O'Donovan

Comment by:  Todd LenczAnil Malhotra (SRF Advisor)
Submitted 11 October 2011 Posted 11 October 2011

It is worth re-emphasizing that efforts such as the Psychiatric GWAS Consortium do not rule out potentially important discoveries from alternative strategies such as endophenotypic approaches or examination of rare variants. Indeed, such strategies will be necessary to understand the functional mechanisms implicated by GWAS hits.

Moreover, we note that the two recently published PGC papers were not designed to exclude a role for previously identified candidate loci such as DISC1 (Hodgkinson et al., 2004), or prior GWAS findings such as rs1344706 at ZNF804A (Williams et al., 2011). For both these loci, and many others that have been proposed, meta-analysis of available samples suggest very small effect sizes (OR ~1.1), as might be expected for common variants. As noted in Supplementary Table S12 of the schizophrenia PGC paper (Ripke et al., 2011), the currently available sample size (~9,000 cases/~12,000 controls) of the discovery cohort was still underpowered to detect variants...  Read more


View all comments by Todd Lencz
View all comments by Anil Malhotra
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