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

Abstract

APOE ɛ4, 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 ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (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 ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- 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 ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- 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 ɛ4 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.

Figure 1

Association of AD with SNPs in chromosome 17q21.31 in the combined stage 1 and stage 2 samples. (A) Regional Manhattan plot in the APOE ε4+ (upper panel) and the APOE ε4− (lower panel) subgroups. SNPs with the lowest P-value are indicated with a purple diamond. Computed estimates of linkage disequilibrium (r²) of SNPs in this region with the most significant SNP are shown as red circles for r² ≥ 0.8, orange circles for 0.6 ≤ r² < 0.8, green circles for 0.4 ≤ r² < 0.6, light blue circles for 0.2 ≤ r² < 0.4, and blue circles for r² < 0.2. Unannotated SNPs are shown as grey circles. (B) Forest plot of association results for rs2732703 in the Stage 1, Stage 2 and total samples among APOE ε4− subjects.

Figure 2

Genotype specific effect of the eQTL rs113986870 on expression of KANSL1. (A) Gene-level expression of KANSL1 transcript t3760137. Transcript-level expression represents the average across all KANSL1 exon probe sets. (B) Expression of exon probe 3760212. Probes 3760211, 3760212, and 3760213 measure expression of the first translated exon, are present in all three transcript variants, and were significantly associated with the eQTL. Expression profiles for probes 3760211 and 3760213 showed similar to those for probe 3760212 (Table 3). The distance from 3760212 to rs113986870 is 85,431 base pairs. Log2 scale of expression (Y-axis) is shown for 10 regions of cognitively normal human brains (X-axis) ordered by mean expression level. Rs113986870 genotype counts: AA=0, AG=56, and GG=76. Rs113986870 allele frequencies are 0.21 (A) and 0.79 (G). CRBL = cerebellum, FCTX = frontal cortex, HIPP = hippocampus, MEDU = medulla (specifically inferior olivary nucleus), OCTX = occipital cortex (specifically primary visual cortex), PUTM = putamen, SNIG = substantia nigra (SNIG), THAL = thalamus, TCTX = temporal cortex), WHMT = intralobular white matter.