Analysis of the joint effect of SNPs to identify independent loci and allelic heterogeneity in schizophrenia GWAS data.

Autor: Polushina T; NORMENT-K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway., Giddaluru S; NORMENT-K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway., Bettella F; NORMENT-K.G. Jebsen Center for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; NORMENT-K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway., Espeseth T; NORMENT-K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.; Department of Psychology, University of Oslo, Oslo, Norway., Lundervold AJ; K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.; Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway., Djurovic S; NORMENT-K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway., Cichon S; Department of Biomedicine, Division of Medical Genetics, University of Basel, Basel, Switzerland.; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University of Bonn, Bonn, Germany.; Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany., Hoffmann P; Department of Biomedicine, Division of Medical Genetics, University of Basel, Basel, Switzerland.; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University of Bonn, Bonn, Germany., Nöthen MM; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University of Bonn, Bonn, Germany., Steen VM; NORMENT-K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway., Andreassen OA; NORMENT-K.G. Jebsen Center for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; NORMENT-K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway., Le Hellard S; NORMENT-K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway. stephanie.hellard@uib.no.; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. stephanie.hellard@uib.no.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2017 Dec 18; Vol. 7 (12), pp. 1289. Date of Electronic Publication: 2017 Dec 18.
DOI: 10.1038/s41398-017-0033-2
Abstrakt: We have tested published methods for capturing allelic heterogeneity and identifying loci of joint effects to uncover more of the "hidden heritability" of schizophrenia (SCZ). We used two tools, cojo-GCTA and multi-SNP, to analyze meta-statistics from the latest genome-wide association study (GWAS) on SCZ by the Psychiatric Genomics Consortium (PGC). Stepwise regression on markers with p values <10 -7 in cojo-GCTA identified 96 independent signals. Eighty-five passed the genome-wide significance threshold. Cross-validation of cojo-GCTA by CLUMP was 76%, i.e., 26 of the loci identified by the PGC using CLUMP were found to be dependent on another locus by cojo-GCTA. The overlap between cojo-GCTA and multi-SNP was better (up to 92%). Three markers reached genome-wide significance (5 × 10 -8 ) in a joint effect model. In addition, two loci showed possible allelic heterogeneity within 1-Mb genomic regions, while CLUMP analysis had identified 16 such regions. Cojo-GCTA identified fewer independent loci than CLUMP and seems to be more conservative, probably because it accounts for long-range LD and interaction effects between markers. These findings also explain why fewer loci with possible allelic heterogeneity remained significant after cojo-GCTA analysis. With multi-SNP, 86 markers were selected at the threshold 10 -7 . Multi-SNP identifies fewer independent signals, due to splitting of the data and use of smaller samples. We recommend that cojo-GCTA and multi-SNP are used for post-GWAS analysis of all traits to call independent loci. We conclude that only a few loci in SCZ show joint effects or allelic heterogeneity, but this could be due to lack of power for that data set.
Databáze: MEDLINE