Genome-wide association study of brain arteriolosclerosis

Lincoln Mp Shade; Yuriko Katsumata; Timothy J Hohman; Kwangsik Nho; Andrew J Saykin; Shubhabrata Mukherjee; Kevin L Boehme; John Sk Kauwe; Lindsay A Farrer; Gerard D Schellenberg; Jonathan L Haines; Richard P Mayeux; Julie A Schneider; Peter T Nelson; David W Fardo

doi:10.1177/0271678X211066299

Genome-wide association study of brain arteriolosclerosis

J Cereb Blood Flow Metab. 2022 Aug;42(8):1437-1450. doi: 10.1177/0271678X211066299. Epub 2022 Feb 14.

Authors

Lincoln Mp Shade¹, Yuriko Katsumata^{1

2}, Timothy J Hohman³, Kwangsik Nho⁴, Andrew J Saykin⁴, Shubhabrata Mukherjee⁵, Kevin L Boehme⁶, John Sk Kauwe⁷, Lindsay A Farrer⁸, Gerard D Schellenberg⁹, Jonathan L Haines¹⁰, Richard P Mayeux¹¹, Julie A Schneider¹², Peter T Nelson^{2

13}, David W Fardo^{1

2}

Affiliations

¹ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
² Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, University of Kentucky, Lexington, KY, USA.
³ Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Department of Medicine, University of Washington, Seattle, WA, USA.
⁶ ARUP Laboratories, Salt Lake City, UT, USA.
⁷ Office of the President, Brigham Young University-Hawaii, Laie, HI, USA.
⁸ Department of Medicine, Boston University, Boston, MA, USA.
⁹ Penn Neurodegeneration Genomics Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰ Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
¹¹ Department of Neurology, Columbia University, New York, NY, USA.
¹² Departments of Neurology and Pathology, Rush University Medical Center, Chicago, IL, USA.
¹³ Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA.

Abstract

Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p = $1.8 \times 10^{- 7}$ ; rs2603462, p = $4 \times 10^{- 7}$ ) were significant in the ADNI cohort (rs7902929, p = $0.012$ ; rs2603462, p = $0.012$ ). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.

Keywords: SVD; VCID; aging; arteriosclerosis; dementia; neuropathology.

MeSH terms

Aged
Alzheimer Disease* / pathology
Arteriolosclerosis* / genetics
Brain / pathology
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide

Abstract

MeSH terms

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