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However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of in vivo assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study of tau-positron emission tomography on a sample of 754 individuals over age 50 (mean age 72.4\u2009years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test nucleotide polymorphism associations with AV-1451 (18F-flortaucipir) tau-positron emission tomography burden in an Alzheimer\u2019s-signature composite region of interest, using an additive genetic model and covarying for age, sex and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (P\u2009=\u20099.91 \u00d7 10\u22129, \u03b2\u2009=\u20090.20) in the tau phosphorylation regulatory gene PPP2R2B (protein phosphatase 2 regulatory subunit B) and for rs117402302 (P \u2009=\u20094.00 \u00d7 10\u22128, \u03b2\u2009=\u20090.19) near IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3). The PPP2R2B association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the IGF2BP3 association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three single nucleotide polymorphisms within MAPT (microtubule-associated protein tau) displayed nominal associations with tau-positron emission tomography burden, and the association of the APOE (apolipoprotein E) \u025b4 allele with tau-positron emission tomography was marginally nonsignificant (P \u2009=\u20090.06, \u03b2\u2009=\u20090.07). No associations with tau-positron emission tomography burden were identified for other single nucleotide polymorphisms associated with Alzheimer\u2019s disease clinical diagnosis in prior large case\u2013control studies. Our findings nominate PPP2R2B and IGF2BP3 as novel potential influences on tau pathology which warrant further functional characterization. Our data are also supportive of previous literature on the associations of MAPT genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer\u2019s susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa159","type":"journal-article","created":{"date-parts":[[2020,9,26]],"date-time":"2020-09-26T16:34:51Z","timestamp":1601138091000},"source":"Crossref","is-referenced-by-count":23,"title":["Variants in<i>PPP2R2B<\/i>and<i>IGF2BP3<\/i>are associated with higher tau deposition"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6591-8734","authenticated-orcid":false,"given":"Vijay K","family":"Ramanan","sequence":"first","affiliation":[{"name":"Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A","family":"Przybelski","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheelakumari","family":"Raghavan","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G","family":"Heckman","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics, Mayo Clinic-Florida, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Batzler","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L","family":"Kosel","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J","family":"Hohman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Knopman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2770-0691","authenticated-orcid":false,"given":"Jonathan","family":"Graff-Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val J","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7177-1185","authenticated-orcid":false,"given":"Michelle M","family":"Mielke","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"},{"name":"Department of Health Sciences Research, Mayo Clinic-Minnesota, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Clifford 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