Novel association strategy with copy number variation for identifying new risk Loci of human diseases.
BACKGROUND
Copy number variations (CNV) are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.


RESULTS
Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP) signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.


CONCLUSIONS
Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases.
Chen
Xianfeng
X
The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Li
Xinlei
X
Wang
Ping
P
Liu
Yang
Y
Zhang
Zhenguo
Z
Zhao
Guoping
G
Xu
Haiming
H
Zhu
Jun
J
Qin
Xueying
X
Chen
Suchao
S
Hu
Landian
L
Kong
Xiangyin
X
D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods*; D056915:DNA Copy Number Variations; D004194:Disease / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
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