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Sci Rep. 2017 Nov 16;7(1):15736. doi: 10.1038/s41598-017-15705-x.

Leveraging genome characteristics to improve gene discovery for putamen subcortical brain structure.

Author information

1
Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, La Jolla, California, 92093, USA. chc101@ucsd.edu.
2
Department of Neurosciences, University of California, San Diego, La Jolla, California, 92093, USA.
3
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
4
Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, La Jolla, California, 92093, USA.
5
Department of Cognitive Science, University of California, San Diego, La Jolla, California, 92093, USA.
6
Department of Radiation Sciences, Umea University, Umea, Sweden.
7
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
8
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
9
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, California, 90027, USA.
10
Division of Biostatistics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, 92093, USA.
11
Department of Psychiatry, University of California, SanDiego, La Jolla, California, 92093, USA.

Abstract

Discovering genetic variants associated with human brain structures is an on-going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5'UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs. The method provides increased power to detect associated SNPs by estimating stratum-specific false discovery rate (FDR), where strata are classified according to enrichment scores. Applying this approach to the GWAS summary statistics of putamen volume in the ENIGMA cohort, a total of 15 independent significant SNPs were identified (conditional FDR < 0.05). In contrast, 4 SNPs were found based on standard GWAS analysis (P < 5 × 10-8). These 11 novel loci include GATAD2B, ASCC3, DSCAML1, and HELZ, which are previously implicated in various neural related phenotypes. The current findings demonstrate the boost in power with the annotation-informed FDR method, and provide insight into the genetic architecture of the putamen.

PMID:
29147026
PMCID:
PMC5691156
DOI:
10.1038/s41598-017-15705-x
[Indexed for MEDLINE]
Free PMC Article

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