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Hum Genet (2015) 134:7787 DOI 10.1007/s00439-014-1494-5
ORIGINAL INVESTIGATION
Renement of schizophrenia GWAS loci using methylome-wide association data
Gaurav Kumar Shaunna L. Clark Joseph L. McClay Andrey A. Shabalin Daniel E. Adkins Linying Xie Robin Chan Srilaxmi Nerella Yunjung Kim Patrick F. Sullivan Christina M. Hultman Patrik K. E. Magnusson Karolina A. Aberg Edwin J. C. G. van den Oord
Abstract Recent genome-wide association studies (GWAS) have made substantial progress in identifying disease loci. The next logical step is to design functional experiments to identify disease mechanisms. This step, however, is often hampered by the large size of loci identied in GWAS that is caused by linkage disequilibrium between SNPs. In this study, we demonstrate how integrating methylome-wide association study (MWAS) results with GWAS ndings can narrow down the location for a subset of the putative casual sites. We use the disease schizophrenia as an example. To handle data analytic variation, we rst combined our MWAS results with two GWAS meta-analyses (N = 32,143 and 21,953), that had largely
overlapping samples but different data analysis pipelines, separately. Permutation tests showed signicant overlapping association signals between GWAS and MWAS ndings. This signicant overlap justied prioritizing loci
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s00439-014-1494-5
Web End =10.1007/s00439-014-1494-5 ) contains supplementary material, which is available to authorized users.
G. Kumar (*) S. L. Clark J. L. McClay A. A. Shabalin D. E. Adkins L. Xie R. Chan S. Nerella K. A. Aberg E. J. C. G. van den Oord
Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Virginia Commonwealth University, McGuire Hall, Room 219, P. O. Box 980533, Richmond, VA 23298-0581, USAe-mail: [email protected]
Y. Kim P. F. Sullivan
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
P. F. Sullivan C. M. Hultman P. K. E. Magnusson
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
Received: 3 June 2014 / Accepted: 28 September 2014 / Published online: 7 October 2014 Springer-Verlag Berlin Heidelberg 2014
based on the concordance principle. To further ensure that the methylation signal was not driven by chance, we successfully replicated the top three methylation ndings near genes SDCCAG8, CREB1 and ATXN7 in an independent sample using targeted pyrosequencing. In contrast to the SNPs...