Common variants conferring risk of schizophrenia


Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders1,2,3. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized4. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

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We thank the subjects and their relatives and staff at the recruitment centres. This work was sponsored by EU grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). Genotyping of the Dutch samples was sponsored by NIMH funding, R01 MH078075. This work was also supported by the National Genomic Network (NGFN-2) of the German Federal Ministry of Education and Research (BMBF) and Marie Curie grant PIAP-GA-2008-218251 (PsychGene). M.M.N. received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. We are grateful to S. Schreiber and M. Krawczak for providing genotype data for PopGen controls, and to K.-H. Jöckel and R. Erbel for providing control individuals from the Heinz Nixdorf Recall Study. Recruitment of the patients from Munich was partially supported by GlaxoSmithKline. We are grateful to the Genetics Research Centre GmbH, an initiative by GlaxoSmithKline and LMU. The Northern Finland Birth Cohort 1966 (NFBC66) is thanked for providing population controls for the study. The genotyping of NFBC66 was financially supported by National Institutes of Health grant 1R01HL087679-01, STAMPEED.

Author Contributions H.S., S.S., D.A.C., D.S.C., D.R., E. Sigurdsson and K.S. wrote the first draft of the paper. M.H., B.B.M., P.M., I.G., H.-J.M., A.H., A.C.N., G.F., N.W., J.L., J. Suvisaari, A.T.-H., T.T., E.B., R.M., M.R., S. Tosato, S.D., I.M., J.O., O.A.A., M.R., R.A.O., L.A.K., O.G., A.D.B., M. Nyegaard, A.F.-J., M. Nordentoft, D.H., B.N.-P., Y.B., R.B., H.B.R., S. Timm, M.M., I.B., J.M.R., L.A., V.K., J. Sanjuan, R.F., E.V., U.E., M.P., J.L.Y., N.B.F., R.M.C., V.G., A.C., C.A., J.C., E.G.J., L.T., I.A., O.M., P.B.M., B.F., T.P. and GROUP recruited, diagnosed and gathered phenotypes. H.S., D.R., R.d.F., E. Strengman, T.S., P.M.M., T.T., J.R.G., U.T., H.P., D.B.G., T.W., D.A.C., L.P., A.K., D.S.C. and K.S. planned, supervised and coordinated the work. S.S., H.S., S.C., P.O., G.M., A.I., T.E.T., O.P.H.P., D.G., K.V.S., M.M.N., T.H. and A.K. analysed the data. All authors contributed to the current version of the paper.

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Correspondence to Kari Stefansson.

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Some of the authors including Kari Stefansson (CEO of deCODE genetics), Jeffrey R. Gulcher (CSO of deCODE genetics) and Augustine Kong (VP Statistics at deCODE genetics) are shareholders in deCODE genetics.

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This file contains Supplementary Methods, Supplementary Tables 1-6, Supplementary Figure 1 with Legend and Supplementary References. (PDF 205 kb)

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