Genome-wide association study identifies four novel loci associated with Alzheimer ’s endophenotypes and disease modifiers

AbstractMore than 20 genetic loci have been associated with risk for Alzheimer ’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased s tatistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with A β42 nearGLIS1 on 1p32.3 (β = −0.059,P = 2.08 × 10−8) and withinSERPINB1 on 6p25 (β = −0.025,P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR  = 1.105,P = 3.43 × 10−2), disease progression (GLIS1:β = 0.277,P = 1.92 × 10−2), and age at onset (SERPINB1:β = 0.043,P = 4.62...
Source: Acta Neuropathologica - Category: Neurology Source Type: research