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

Abstract

More 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 statistical 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 Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 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 (SER-PINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

A/T/N polygenic risk score for cognitive decline in old age

“…We utilized data from a GWAS for CSF biomarkers published by Deming and colleagues [20]. The original data for this study was collected from 3,146 individuals across nine cohort studies, including ADNI.…”

“…Additionally, the National Institute on Aging and Alzheimer's Association released a research framework for AD in which the pathological accumulation of amyloid plaques (A), neurofibrillary tangles composed of tau (T), and neurodegeneration (N) are recommended to be included in diagnostic categories of AD used for research [19]. While this A/T/N framework has emerged in studies of preclinical disease, it has not been integrated into PRS for AD despite the availability of GWAS summary statistics for autopsy and in vivo measures of A/T/N [20,21]. Indeed, a previous study suggested that shared genetic drivers for hippocampal volume (a marker of neurodegeneration) and AD may exist [22].…”

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

“…ApoE has been shown to directly bind tau in vitro 6 , and neuronal expression of human ApoE in vivo results in tau hyperphosphorylation (E4>E3) 7 . Recent GWAS studies show a strong and significant association of APOE with CSF tau and p-tau after correcting for the effect of APOE on Aβ42 levels 8 . In frontotemporal dementia (FTD) patients, a large percentage of whom have tauopathy, ε4 allele frequency was reported to be significantly elevated 9,10 , and ε4 carriers have greater atrophy in affected brain regions 11 as well as exacerbated behavioral deficits 12 .…”

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

“…Rs476155 was identified as a susceptibility locus for low HDL-cholesterol levels, a risk factor for coronary artery disease in ethnic Arabs [84]. A significant association was also found between the GLIS3 SNP, rs514716, and elevated levels of cerebrospinal fluid (CSF) tau and phosphorylated tau (ptau 181 ), established biomarkers for AD [85, 86]. No significant correlation was found between T2D-associated GLIS3 SNP, rs10814916, and risk of Parkinson’s or Alzheimer’s disease (AD) [87].…”

“…GLIS1 variants have been reported to be a risk factor for several neural pathologies. The intergenic SNP, rs185031519, near the GLIS1 locus was found to be associated with lower cerebrospinal fluid (CSF) amyloid-beta1–42 (Aβ 42 ) levels and higher tau and phosphorylated tau (ptau 181 ) levels [86]. Lower CSF Aβ 42 levels and higher tau and ptau 181 correlate with the number of neurofibrillary tangles and plaque load and are well-established AD endophenotypes.…”