Hidden risk genes with high-order intragenic epistasis in Alzheimer's disease.
Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD.
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Jiya
J
Sun
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Fuhai
F
Song
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Jiajia
J
Wang
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Guangchun
G
Han
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Zhouxian
Z
Bai
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
Bin
B
Xie
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Xuemei
X
Feng
Center of Alzheimer's disease, Beijing Institute for Brain Disorders, Beijing, China Department of Neurology, Xuanwu hospital, Beijing, China.
Jianping
J
Jia
UC Davis Genome Center and Department of Biomedical Engineering, Davis, CA, USA.
Yong
Y
Duan
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China Center of Alzheimer's disease, Beijing Institute for Brain Disorders, Beijing, China UC Davis Genome Center and Department of Biomedical Engineering, Davis, CA, USA.
Hongxing
H
Lei
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D011962:Receptors, FSH / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D001057:Apolipoproteins E; D002352:Carrier Proteins; C470936:KIRREL3 protein, human; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; C561839:NR3C2 protein, human; D009419:Nerve Tissue Proteins; D011962:Receptors, FSH; D018161:Receptors, Mineralocorticoid; D019837:Ryanodine Receptor Calcium Release Channel; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517265:PDE1A protein, human
Alzheimer's disease; generalized multifactor dimensionality reduction; genetic risk; high-order; intragenic epistasis