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ObjectiveWe sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.MethodsWe performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.ResultsWe detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.ConclusionsWhole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

Background and Objectives: The objective of this study was to determine the relationship between plasma β-amyloid (Aβ), specifically the ratio of 2 Aβ peptides (the Aβ 42 /Aβ 40 ratio, which correlates with increased accumulation of Aβ in the CNS), and late-onset epilepsy (LOE)., Methods: We used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aβ 42 /Aβ 40 ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aβ 42 /Aβ 40 , and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aβ peptides, the Aβ 42 /Aβ 40 ratio, correlates with low CSF Aβ 42 /Aβ 40 and with increased accumulation of Aβ in the CNS., Results: Decrease in plasma Aβ 42 /Aβ 40 ratio from midlife to late life, but not an isolated measurement of Aβ 42 /Aβ 40 , was associated with development of epilepsy in later life. For every 50% reduction in Aβ 42 /Aβ 40 , there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17)., Discussion: A reduction in plasma Aβ 42 /Aβ 40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aβ, hyperexcitable states, and LOE., (© 2023 American Academy of Neurology.)