| Autor: |
Dang, Lam‐Ha T, Petersen, Melissa, Xicota, Laura, O'Bryant, Sid E., Krinsky‐McHale, Sharon J, Mapstone, Mark, Kamboh, M. Ilyas, Cruchaga, Carlos, Handen, Benjamin L., Pang, Deborah, Silverman, Wayne, Schupf, Nicole, Lee, Joseph H. |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 14, Vol. 19, p1-2, 2p |
| Abstrakt: |
Background: Only a few studies in the general population have investigated genetic contributions to variation in levels of neurofilament light (NfL), which is a general marker of axonal damage and is predictive of Alzheimer's disease (AD). To our knowledge, no studies have examined this relation in people with Down Syndrome (DS), a population at high risk of developing AD. We performed a genome‐wide search for SNPs associated with plasma NfL levels. We paid special attention to genetic variants identified in the general population to be associated with AD risk and NfL to evaluate whether those variants contributed to AD in DS by altering NfL levels. Methods: We performed a meta‐analysis using two datasets (N = 455): the omicsADDS and ABC‐DS studies. Levels of plasma NfL were measured using the Simoa platform and genotyping was performed using an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 was performed using the TOPMed Imputation Server. We first assessed the association between SNPs and plasma NfL levels in each dataset using a multivariable linear regression model that included age, sex, dementia status, and genetic ancestry. We then performed meta‐analysis using sample size weighting. We restricted our meta‐analysis to variants that had study‐specific P<5×10−4, to minimize potential false positives. Results: Our genome‐wide scan, after Bonferroni correction, identified 33 novel SNPs contributing to variation in plasma NfL (28 variants with elevated plasma NfL and 5 variants with decreased plasma NfL). Three AD‐risk variants previously identified in the general population (UNC5CL/rs10947943, USP6NL/rs7912495, FOXF1/rs16941239), were found to be associated with variation in plasma NfL levels at nominal Pmeta < 0.05. Candidate variants associated with NfL in the general population were not replicated in the current meta‐analysis. The novel genes identified have been implicated in tau neuropathology, variation in lipid levels, insulin regulation, and neurotransmitter release. Conclusion: This genome‐wide meta‐analysis revealed multiple novel genetic loci associated with NfL levels in plasma in adults with DS. We additionally found supporting evidence for three known variants. The genes identified here may lead to insight into underlying mechanisms of neurodegeneration and AD in adults with DS. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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