Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

Abstract

BACKGROUND:Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS). METHODS:Three sets of summary statistics were included in our meta-GWAS of AD: an Spanish casecontrol study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inversevariance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of subthreshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study. FINDINGS:Using our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical ADcase control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10 -7 ), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10 -39 ). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12-4.18, p = 3.2×10 -10 ) increased risk compared to those with the 2% lowest risk (p = 5.9×10 -10 ). Using the PRS we identified APOE ɛ33 carriers with a similar risk as APOE ɛ4 heterozygotes carriers, as well as APOE ɛ4 heterozygote carriers with a similar risk as APOE ɛ4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10 -6 ); a 4-year median onset diff...

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

“…In recent years, genome-wide association studies (GWASs) reinforce that AD is a complex disease, in which APP processing and immune response play key roles [212]. Whole genome sequencing (WGS), GWAS, and gene-expression network analysis proved that LOAD genetics implicates microglial pathways and CR1, SII1, MS4As, TREM2, ABCA7, CD33, INPP5D genes are associated with disease risk [212]. The results of the largest meta-GWAS approach (analyzing 19,089 AD cases) and follow-up analysis for AD risk has been published very recently [212].…”

“…Whole genome sequencing (WGS), GWAS, and gene-expression network analysis proved that LOAD genetics implicates microglial pathways and CR1, SII1, MS4As, TREM2, ABCA7, CD33, INPP5D genes are associated with disease risk [212]. The results of the largest meta-GWAS approach (analyzing 19,089 AD cases) and follow-up analysis for AD risk has been published very recently [212]. It was found that altogether 39 genetic variants may be associated with AD risk (beyond the APOE variants).…”

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

“…However, previous studies to determine roles of GWAS genes in AD have primarily been limited to the B6 genetic background. Therefore, we aimed to determine whether our wild-derived AD panel provided an enhanced platform to study human-relevant AD genes using a panel of 54 GWAS genes identified in two recent meta-analyses ( Supplementary Table 6 ) 31,32 . A total of 36 microglia-relevant genes were detectable across our panel.…”

“…The human AD GWAS genes were selected from two recent meta-analyses (Table 1 31 and Table S2 32 ). The GWAS genes from both tables were combined and were overlapped with equivalent mouse genes in scRNA-seq data from this study.…”

Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

“…Apolipoprotein ε4 allele (APOE4) is the only common high risk genetic variant (odds ratio (OR)=3.32) (11,12). Genome wide association studies (GWAS) have further identified many common genetic variants with low risk (OR=1.1-1.2) of which 40 have genome wide significance (12)(13)(14). Exome chip analyses have additionally yielded rare variants in the very same genes, i.e.…”