期刊
GENETICS
卷 203, 期 2, 页码 715-+出版社
GENETICS SOCIETY AMERICA
DOI: 10.1534/genetics.115.186502
关键词
adaptive association test; ADNI; default mode network; gene-based test; imaging genetics; multiple traits
资金
- National Institutes of Health (NIH) [R01GM113250, R01HL105397, R01HL116720]
- Minnesota Supercomputing Institute
- University of Minnesota Informatics Institute MnDRIVE fellowship
- Alzheimer's Disease Neuroimaging Initiative (ADNI) [U01 AG024904]
- Department of Defense (DOD) ADNI (DOD award) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Association
- Alzheimers Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen Idec, Inc.
- Bristol-Myers Squibb Company
- Eisai, Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development, LLC.
- Medpace, Inc.
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer, Inc.
- Piramal Imaging
- Servier
- Synarc, Inc.
- Takeda Pharmaceutical Company
- Canadian Institutes of Rev Health Research
Testing for genetic association with multiple traits has become increasingly important, not only because of its potential to boost statistical power, but also for its direct relevance to applications. For example, there is accumulating evidence showing that some complex neurodegenerative and psychiatric diseases like Alzheimer's disease are due to disrupted brain networks, for which it would be natural to identify genetic variants associated with a disrupted brain network, represented as a set of multiple traits, one for each of multiple brain regions of interest. In spite of its promise, testing for multivariate trait associations is challenging: if not appropriately used, its power can be much lower than testing on each univariate trait separately (with a proper control for multiple testing). Furthermore, differing from most existing methods for single-SNP-multiple-trait associations, we consider SNP set-based association testing to decipher complicated joint effects of multiple SNPs on multiple traits. Because the power of a test critically depends on several unknown factors such as the proportions of associated SNPs and of traits, we propose a highly adaptive test at both the SNP and trait levels, giving higher weights to those likely associated SNPs and traits, to yield high power across a wide spectrum of situations. We illuminate relationships among the proposed and some existing tests, showing that the proposed test covers several existing tests as special cases. We compare the performance of the new test with that of several existing tests, using both simulated and real data. The methods were applied to structural magnetic resonance imaging data drawn from the Alzheimer's Disease Neuroimaging Initiative to identify genes associated with gray matter atrophy in the human brain default mode network (DMN). For genome-wide association studies (GWAS), genes AMOTL1 on chromosome 11 and APOE on chromosome 19 were discovered by the new test to be significantly associated with the DMN. Notably, gene AMOTL1 was not detected by single SNP-based analyses. To our knowledge, AMOTL1 has not been highlighted in other Alzheimer's disease studies before, although it was indicated to be related to cognitive impairment. The proposed method is also applicable to rare variants in sequencing data and can be extended to pathway analysis.
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