Polygenic Analysis of Late-Onset Alzheimer's Disease from Mainland China.

Bin Jiao,Beisha Tang,Xiaoyan Liu,Rui Sun,Weiwei Zhang,Maggie Haitian Wang,Yafang Zhou,Mary Miu Yee Waye,Lu Shen,Lin Zhou,Tingting Xiao,Riqiang Yan

doi:10.1371/journal.pone.0144898

Abstract

Recently, a number of single nucleotide polymorphisms (SNPs) were identified to be associated with late-onset Alzheimer disease (LOAD) through genome-wide association study data. Identification of SNP-SNP interaction played an important role in better understanding genetic basis of LOAD. In this study, fifty-eight SNPs were screened in a cohort of 229 LOAD cases and 318 controls from mainland China, and their interaction was evaluated by a series of analysis methods. Seven risk SNPs and six protective SNPs were identified to be associated with LOAD. Risk SNPs included rs9331888 (CLU), rs6691117 (CR1), rs4938933 (MS4A), rs9349407 (CD2AP), rs1160985 (TOMM40), rs4945261 (GAB2) and rs5984894 (PCDH11X); Protective SNPs consisted of rs744373 (BIN1), rs1562990 (MS4A), rs597668 (EXOC3L2), rs9271192 (HLA-DRB5/DRB1), rs157581 and rs11556505 (TOMM40). Among positive SNPs presented above, we found the interaction between rs4938933 (risk) and rs1562990 (protective) in MS4A weakened their each effect for LOAD; for three significant SNPs in TOMM40, their cumulative interaction induced the two protective SNPs effects lost and made the risk SNP effect aggravate for LOAD. Finally, we found rs6656401-rs3865444 (CR1-CD33) pairs were significantly associated with decreasing LOAD risk, while rs28834970-rs6656401 (PTK2B-CR1), and rs28834970-rs6656401 (PTK2B-CD33) were associated with increasing LOAD risk. In a word, our study indicates that SNP-SNP interaction existed in the same gene or cross different genes, which could weaken or aggravate their initial single effects for LOAD.

Highlights

Alzheimer’s disease (AD) is a clinically complex neurodegenerative disorder, affecting up to 81.1 million people worldwide [1]
Among positive SNPs presented above, we found the interaction between rs4938933 and rs1562990 in MS4A weakened their each effect for late-onset Alzheimer disease (LOAD); for three significant SNPs in TOMM40, their cumulative interaction induced the two protective SNPs effects lost and made the risk SNP effect aggravate for LOAD
13 significantly different allelic frequencies were identified between patients and controls after adjusting age and gender, including seven risk SNPs and six protective SNPs for LOAD

Summary

Introduction

Alzheimer’s disease (AD) is a clinically complex neurodegenerative disorder, affecting up to 81.1 million people worldwide [1]. At least two methods are suggested to identify the risk gene variants for LOAD, including Whole Exome Sequence (WES) and genome-wide association study (GWAS) [7,8]. The former is mainly to identify rare coding variants, such as rs75932628 in TREM2, rs145999145 in PLD3 and rs137875858 in UNC5C, which were recently recognized as risk variants for LOAD [7,9,10,11]. A polygenic analysis has been suggested to explain genetic contribution to the pathogenesis of the majority of LOAD cases. Even if some variants had no effect on LOAD, their interactions could become significant effects associated with LOAD

Materials and Methods

Genotyping methods

Statistical methods

Results

Discussion