biostudies-literatureVattathil SMNational Institute of Neurological Disorders and StrokeBLRD VANIA NIH HHSNIMH NIH HHSNINDS NIH HHSNational Institute of Mental HealthU.S. Department of Veterans AffairsNational Institute on Aging815https://www.ebi.ac.uk/biostudies/studies/S-EPMC8228534biostudies-literatureUnknown12(6)Cerebral 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 <i>NTNG1</i>. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (<i>β</i> = -0.27, 95% CI = (-0.35, -0.19), <i>p</i> = 1.29 × 10^-10) and rs10881463 (<i>β</i> = -0.20, 95% CI = (-0.27, -0.13), <i>p</i> = 3.40 × 10^-8). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4-NOT, 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.GenesA Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with <i>NTNG1</i> and CNOT3.PMC8228534R01 AG057911P30 AG053760P50 AG005146P50 AG005142P50 AG047266I01 BX003853P30 AG019610P30 AG066444R56 AG062633P50 AG008702P30 AG010124R01 AG061800P30 AG012300P50 AG047270P30 AG010161U01 AG61356R01 AG053960P30 AG049638RC2 AG036547U01 AG032984U24 AG041689U01 AG061356R01 AG015819P30 AG013846P30 AG028383P30 AG008017U01 AG061357P30 AG010133P50 AG033514P50 AG005681P30 NS055077P50 AG047366U24 NS072026R56 AG062256P50 AG023501P30 AG008051P30 AG010129P30 AG013854P50 AG005138RF1 AG057470P50 AG005134P50 AG005136P50 AG025688U01 AG016976P30 AG035982R56 AG060757P50 AG005131P50 AG005133R01 AG056533P50 AG016574U01 AG046161P50 AG016573R01 AG017917U01 MH115484R01 AG042210Wingo APLevey AIHarerimana NVLiu YSeyfried NTWingo TSGerasimov ESSchneider JABennett DAVattathil SMLori ABeach TGReiman EMDe Jager PLfalseA Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with <i>NTNG1</i> and CNOT3.Cerebral 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 <i>NTNG1</i>. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (<i>β</i> = -0.27, 95% CI = (-0.35, -0.19), <i>p</i> = 1.29 × 10^-10) and rs10881463 (<i>β</i> = -0.20, 95% CI = (-0.27, -0.13), <i>p</i> = 3.40 × 10^-8). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4-NOT, 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.2021-01-01T00:00:00Z2021 May2025-05-31T23:50:03.139Z2025-05-31T23:50:03.139ZS-EPMC82285343407361910.3390/genes12060815