Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels

Introduction: MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. Methods: We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. Results: H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). Conclusions: These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression

Novel late-onset Alzheimer disease loci variants associate with brain gene expression

OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 × 10(−4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(−4)–1.86 × 10(−4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(−5)–9.09 × 10(−9)), some of which also associate with AD risk (p = 2.64 × 10(−2)–6.25 × 10(−5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci

Summary of brain eGWAS and human disease associations.

<p>Summary of brain eGWAS and human disease associations.</p

Validation of top cerebellar <i>cis</i>SNP/transcript associations in the temporal cortex.

<p>Of the 2,980 top <i>cis</i>SNP/transcript associations, 2,685 existed in the temporal cortex replication study. Some of these top associations are shown. Only one <i>cis</i>SNP/transcript pair is selected for depiction. The chromosome (CHR), SNP, Probe, Gene Symbol (SYMBOL) of these associations are depicted. The uncorrected (P), genome-wide (P_Bonf) and study-wide Bonferroni-corrected (P_Bonf-study) P values, Beta coefficient of association are shown for the combined (All) analyses in the cerebellar eGWAS and the temporal cortex replication study. Regression coefficients are based on the SNP minor allele using an additive model.</p

Variance of cerebellar probe expression levels due to technical, biological, and <i>cis</i>SNP effects.

<p>Results from some of the top probes are depicted. Only one probe is selected per gene for depiction. R2technical = variance due to technical variables only (i.e. plates, RIN). addR2covariates = added proportion of variance due to biological covariates (i.e. age, sex, ApoE4 dose), adjR2covariates = addR2covariates adjusted for technical variance, addR2best-SNP = proportion of variance due to the best <i>cis</i>SNP, adjR2best-SNP = addR2best-SNP adjusted for technical variance.</p