Dataset Information

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

ABSTRACT:

Background

Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown.

Results

We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P<5×10^-8) (top SNP, rs7921574; β =0.06, P=1.54×10^-8). This locus mapped to an intron of CNNM2. A trans-ancestry GWAS meta-analysis identified two more loci at NT5C2 (rs10748839; P=2.54×10^-8) and at AS3MT (rs10786721; P=4.97×10^-8), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of CNNM2 (rs7897654, β=0.12, P=6.17×10^-7) and AL356608.1 (rs10786719, β =-0.17, P=6.60×10^-6) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of TCF25 were identified (top SNP, rs35994878; β =0.11, P=2.94×10^-8). For the anterior brain arterial diameter, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10^-8).

Conclusion

Our study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.

SUBMITTER: Liu M

PROVIDER: S-EPMC9915818 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

Liu Minghua M Khasiyev Farid F Sariya Sanjeev S Spagnolo-Allende Antonio A Sanchez Danurys L DL Andrews Howard H Yang Qiong Q Beiser Alexa A Qiao Ye Y Thomas Emy A EA Romero Jose Rafael JR Rundek Tatjana T Brickman Adam M AM Manly Jennifer J JJ Elkind Mitchell Sv MS Seshadri Sudha S Chen Christopher C Sacco Ralph L RL Hilal Saima S Wasserman Bruce A BA Tosto Giuseppe G Fornage Myriam M Gutierrez Jose J

medRxiv : the preprint server for health sciences 20230215

<h4>Background</h4>Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown.<h4>Results</h4>We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial dia ...[more]

PMID: 36778463

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Project description:Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P?=?0.0005). Using a subset of individuals with prospectively measured arsenic (n?=?769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P?=?0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P?=?10(-12)) and neighboring gene C10orf32 (P?=?10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.

Dataset Information

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

Background

Results

Conclusion

Publications

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

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