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Genome‐wide association study of tau‐PET: Association of variant near NTNG2 with resistance to tau deposition
Author(s) -
Ramanan Vijay K.,
Wang Xuewei K,
Przybelski Scott A.,
Pillai Sheela Kumari Raghavan,
Kosel Matthew L.,
Batzler Anthony K.,
Knopman David S.,
Radford Jonathan Graff,
Lowe Val J.,
Mielke Michelle M.,
Jack Clifford R.,
Petersen Ronald C.,
Ross Owen A.,
Vemuri Prashanthi
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044321
Subject(s) - genome wide association study , single nucleotide polymorphism , linkage disequilibrium , genetic association , biology , genetics , expression quantitative trait loci , genotype , gene
Background Tau deposition is a key biological feature of Alzheimer’s disease (AD) that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau accumulation while others are more resistant. The recent availability of tau positron emission tomography (tau‐PET) provides an opportunity to test the hypothesis that genetic factors are associated with differential tau deposition. Methods We performed a genome‐wide association study (GWAS) of tau‐PET on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.4% cognitively unimpaired) from the population‐based Mayo Clinic Study of Aging. Following genotyping with the Illumina GSA array and standard quality control, 515,206 single nucleotide polymorphisms (SNPs) were tested for association with entorhinal cortex 18 F‐flortaucipir tau‐PET burden using linear regression under an additive genetic model and covarying for age and sex. Result A genome‐wide significant association was identified for rs75546066, an intergenic SNP on chromosome 9 between MED27 (mediator complex subunit 27) and NTNG2 (netrin G2), with the minor (A) allele associated with lower tau burden ( p =2.85 x 10 ‐8 , β=‐0.48). Linkage disequilibrium and public expression quantitative trait loci (eQTL) data suggested a functional relationship between rs75546066 and NTNG2 , the latter of which is highly expressed in the brain. In addition to this novel finding, three SNPs within MAPT (microtubule‐associated protein tau) displayed nominal associations to tau‐PET burden, including rs3785883 ( p =0.04, β=0.07) which was previously associated with higher cerebrospinal fluid tau in an independent cohort. No associations with tau‐PET burden were identified for the APOE (apolipoprotein E) ɛ4 or ɛ2 alleles or for genotyped SNPs previously associated with AD in large case‐control studies. Conclusion To our knowledge, this study represents the first reported neuroimaging GWAS of tau pathology. Our findings confirm the association of MAPT with tau burden and nominate the rs75546066‐ NTNG2 locus as a novel potential protective influence against tau pathology which warrants further functional characterization. Our data also supports the inference that tau accumulation may have a genetic architecture distinct from APOE and other known AD susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting models.