Genome‐wide association meta‐analysis of plasma neurofilament light levels in high‐risk adults with Down Syndrome

• DOI: 10.1002/alz.079001
• Publication Date: 2023-12-25T06:05:50Z
• Authors: Lam‐Ha T Dang; Melissa Petersen; Laura Xicota; Sid E. O'Bryant; Sharon J Krinsky‐...; Mark Mapstone; M. Ilyas Kamboh; Carlos Cruchaga; Benjamin L. Handen; Deborah Pang; Wayne Silverman; Nicole Schupf; Joseph H. Lee
• Keywords: Genome-wide Association Study; Genetic Association; Imputation (statistics); Bonferroni correction; Population stratification

Abstract Background Only a few studies in the general population have investigated genetic contributions to variation levels of neurofilament light (NfL), which is marker axonal damage and predictive Alzheimer’s disease (AD). To our knowledge, no examined this relation people with Down Syndrome (DS), at high risk developing AD. We performed genome‐wide search for SNPs associated plasma NfL levels. paid special attention variants identified be AD evaluate whether those contributed DS by altering Methods meta‐analysis using two datasets (N = 455): omicsADDS ABC‐DS studies. Levels were measured Simoa platform genotyping was an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 TOPMed Server. first assessed association between each dataset multivariable linear regression model that included age, sex, dementia status, ancestry. then sample size weighting. restricted had study‐specific P<5×10 −4 , minimize potential false positives. Results Our scan, after Bonferroni correction, 33 novel contributing (28 elevated 5 decreased NfL). Three AD‐risk previously ( UNC5CL /rs10947943, USP6NL /rs7912495, FOXF1/ rs16941239), found nominal P meta < 0.05. Candidate not replicated current meta‐analysis. The genes been implicated tau neuropathology, lipid levels, insulin regulation, neurotransmitter release. Conclusion This revealed multiple loci adults DS. additionally supporting evidence three known variants. here may lead insight into underlying mechanisms neurodegeneration