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

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE 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 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 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 data sets (best SNP, rs2732703, P=5·8 × 10-9). 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=1·6 × 10-7) 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≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). 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 with 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

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease

Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.</p

New genome-wide significant genes associated with AD in the vicinity of recently reported single SNP genome-wide significant hits[9], [19].

<p>Gene-wide p-values are shown for those genes with p<2.5×10⁻⁶ for which the best single-SNP p-value in that gene is greater than 5×10⁻⁸ in the combined Stage 1 and Stage 2 sample. Previously reported genes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094661#pone.0094661-Harold1" target="_blank">[4]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094661#pone.0094661-Seshadri1" target="_blank">[8]</a> ± 0.5 Mb around them are excluded.</p><p>Gene-wide p-values in the combined Stage 1 and Stage 2 sample obtained by combining the p-values from the Stage 1 with those from the Stage 2 using Fisher's method. The LD between rs1476679 (chr7∶100,004,446) reported by IGAP <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094661#pone.0094661-Lambert2" target="_blank">[9]</a> and the best SNP in ZNF3 is r² = 0.16. The LD between rs10838725 (chr11: 47,557,871) reported by IGAP <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094661#pone.0094661-Lambert2" target="_blank">[9]</a> and the best SNPs in the region on chr 11 in the table are r² = 0.3 and 0.88 for <i>NDUFS3</i> and <i>MTCH2</i> respectively.</p

Overrepresentation of significant loci, excluding regions of 0.5[4]–[8] and Stage 1 IGAP genes[9], [19] containing genome-wide significant SNPs.

<p>The observed number of genes is calculated by combining significant loci within 0.5 Mb into one signal. The APOE region is excluded (CHR19; 44,411,940–46,411,945bp). The total number of genes after exclusions is 24,849.</p

New genome-wide significant genes associated with AD.

<p>Gene-wide p-values are shown for those genes with p<2.5×10⁻⁶ for which the best single-SNP p-value in that gene is greater than 5×10⁻⁸ in the combined Stage 1 and Stage 2 sample. Previously reported genes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094661#pone.0094661-Harold1" target="_blank">[4]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094661#pone.0094661-Seshadri1" target="_blank">[8]</a> ± 0.5 Mb around them are excluded.</p><p>Gene-wide p-values in the combined Stage 1 and Stage 2 sample obtained by combining the p-values from the Stage 1 with those from the Stage 2 using Fisher's method.</p