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atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in NTNG1. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (\u03b2 = \u22120.27, 95% CI = (\u22120.35, \u22120.19), p = 1.29 \u00d7 10\u221210) and rs10881463 (\u03b2 = \u22120.20, 95% CI = (\u22120.27, \u22120.13), p = 3.40 \u00d7 10\u22128). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4\u2212NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.<\/jats:p>","DOI":"10.3390\/genes12060815","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T21:56:44Z","timestamp":1622066204000},"page":"815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with NTNG1 and CNOT3"],"prefix":"10.3390","volume":"12","author":[{"given":"Selina M.","family":"Vattathil","sequence":"first","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia V.","family":"Harerimana","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Lori","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina S.","family":"Gerasimov","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[{"name":"Department of Pathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Reiman","sequence":"additional","affiliation":[{"name":"Banner Alzheimer\u2019s Institute, Arizona State University and University of Arizona, Phoenix, AZ 85351, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[{"name":"Center for Translational and Computational Neuroimmunology, Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4507-624X","authenticated-orcid":false,"given":"Nicholas T.","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan I.","family":"Levey","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliza P.","family":"Wingo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Division of Mental Health, Atlanta VA Medical Center, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-6282","authenticated-orcid":false,"given":"Thomas S.","family":"Wingo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev.genom.5.061903.175930","article-title":"Genetics of atherosclerosis","volume":"5","author":"Lusis","year":"2004","journal-title":"Annu. 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