A novel Alzheimer disease locus located near the gene encoding tau protein

Abstract

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

“…; 2,451 cases and 2,063 controls) [41] . Second, the re-analysis of IGAP data after stratification on the APOE genotype unraveled a locus located near the MAPT gene which encodes the Tau protein [42] , which still remains to be replicated in independent studies. Last, a gene-wide analysis of IGAP data revealed two more hits ( TP53INP1 , p = 1.4 × 10 -6 , and IGHV1-67 , p = 7.9 × 10 -8 ) [43] .…”

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

“…They found, that the ' A' allele of rs393152, within the CRHR1 and CRHR1-IT1 region (MAPT locus) on chromosome 17, with a MAF (minor allele frequency) value of 23.1%, significantly increased AD and PD risk, additionally, that allele is linked to the up-regulation of MAPT expression [33]. With APOE-stratified GWAS, another study revealed that genetic variants in the chromosome 17q21.31 region are associated with AD [59].…”

Precision Medicine

“…In 2013, the International Genomics of Alzheimer's Project reported results from >74,000 individuals that brought to 21 the total number of genetic susceptibility loci for a clinical diagnosis of AD dementia, 30 and more have been discovered since. 31,32 It is important to recognize that these genomic studies have linked genetic variants with the clinical diagnosis of AD dementia. Recognizing that the clinical expression of AD dementia is the culmination of stress and injury, response to injury, consumption of reserve, and compensation, we sought to clarify the mechanisms underlying genetic susceptibility for AD dementia by determining their association with SPs and NFTs.…”