New insights into the genetic etiology of Alzheimer’s disease and related dementias

Abstract

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

African Ancestry GWAS of Dementia in a Large Military Cohort Identifies Significant Risk Loci

“…There were also 15 suggestive (p<5.0x10 -7 ) associations including SNPs near CD2AP (rs7738720), TREM2 (rs2234253), and ABCA7 (rs73505251) that were previously established as AD genes in EUR subjects (see Table 1 for details). Importantly, none of these were the same SNPs identified in recent GWASs in EUR cohorts [7][8][9][10] . Gene-based tests yielded one genome-wide significant association with TREM2 (Bonferroni-corrected p=0.02), consistent with the significant TREM2 gene-based association observed by Kunkle et al 12 Adjustment for APOE ε4 did not yield any genome-wide significant associations, but seven variants reached the suggestive level (Supplementary Table 3), including SNPs in or near LHX6 (rs181518405, p=3.90x10 -7 ), CFAP46 (rs146777408, p=3.34x10 -7 ), and OCSTAMP (rs202380, p=2.98x10 -7 ).…”

“…Genome-wide association studies (GWASs) of EUR cohorts have increased our knowledge of the genetic architecture of AD beyond the APOE locus [7][8][9] . The most recent largescale EUR GWAS of AD by Bellenguez et al 10 , reported 75 AD risk loci in addition to APOE.…”

“…Genome-wide association studies (GWASs) of EUR cohorts have increased our knowledge of the genetic architecture of AD beyond the APOE locus 7–9 . The most recent large-scale EUR GWAS of AD by Bellenguez et al 10 , reported 75 AD risk loci in addition to APOE . Their study included 20,464 AD cases and 22,244 controls as well as n=46,828 “proxy” dementia cases in which case status was determined based on a reported history of AD or dementia in one or both parents.…”

Whole genome analysis in APOE4 homozygotes identifies the DAB1-RELN pathway in Alzheimer’s disease pathogenesis

“…APOE -ε4 carriers have elevated risk for AD and earlier age-at-onset, with APOE- ε4 homozygotes at the highest risk [37, 38]. Many loci beyond APOE have been reported as associated with disease in increasingly large GWAS and meta-analyses, with over 80 susceptibility loci reported collectively [4, 39, 40]. We find no evidence to support the role of additional loci in an extended 2Mb region around APOE in APOE- ε4 homozygotes.…”

Mosaic patterns of selection in genomic regions associated with diverse human traits

“…This result held across five published GWASs of late-onset Alzheimer's disease. The GWASs had between 19 to 132 trait-associated regions identified in European-ancestry populations: Bellenguez 44 , Marioni 45 , Kunkle 46 , GRACE 47 , IGAP 48 . Across the 11 evolutionary measures we tested, all GWASs had trait-associated evolutionary values that overlap the expected range from their matched backgrounds (p>0.05, Figure 4).…”