Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Abstract

IntroductionLate-onset Alzheimer's disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) [3][4][5][6][7][8] . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10 -7 ) indicating that additional rare variants remain to be identified. Main TextOur previous work identified 19 genome-wide significant common variant signals in addition to APOE 9 , that influence risk for LOAD. These signals, combined with 'subthreshold' common variant associations, account for ~31% of the genetic variance of LOAD 2 , leaving the majority of genetic risk uncharacterized 10 . To search for additional signals, we conducted a GWAS metaanalysis of non-Hispanic Whites (NHW) using a larger sample (17 new, 46 total datasets) from our group, the International Genomics of Alzheimer's Project (IGAP) (composed of four AD consortia: ADGC, CHARGE, EADI, and GERAD). This sample increases our previous discovery sample (Stage 1) by 29% for cases and 13% for controls (N=21,982 cases; 41,944 controls) ( Supplementary Table 1 and 2, and Supplementary Note). To sample both common and rare variants (minor allele frequency MAF ≥ 0.01, and MAF < 0.01, respectively), we imputed the discovery datasets using a 1000 Genomes reference panel consisting of . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a 11 36,648,992 single-nucleotide variants, 1,380,736 insertions/deletions, and 13,805 structural variants. After quality control, 9,456,058 common variants and 2,024,574 rare variants were selected for analysis (a 63% increase from our previous common variant analysis in 2013).Genotype dosages were analyzed within each dataset, and then combined with meta-analysis ( Supplementary Figures 1 and 2 and Supplementary Table 3). The Stage 1 discovery metaanalysis was first followed by Stage 2 using the I-select chip we previously developed in Lambert et al (including 11,632 variants, N=18,845) and finally stage 3A (N=6,998). The final sample was 33,692 clinical AD cases and 56,077 controls.Meta-analysis of Stages 1 and 2 produced 21 associations with P ≤ 5x10 -8 (Table 1 and Figure 1). Of these, 18 were previously reported as genome-wide significant and three of them are signals not initially described in Lambert et al: the rare R47H TREM2 coding va...

Lipid lowering and Alzheimer disease risk: A mendelian randomization study

“…The total sample size was 24,718 cases and 56,685 controls, all of whom had European ancestry (summary details are given in Table ). Full information on genetic quality control procedures and association modeling are provided in the study references …”

“…We assessed whether LDL-associated variants also associate with late onset AD risk (age of onset ≥65 years) using data from 2 large genome-wide analyses from the International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium (PGC). 19,20 The total sample size was 24,718 cases and 56,685 controls, all of whom had European ancestry (summary details are given in Table 1). Full information on genetic quality control procedures and association modeling are provided in the study references.…”

“…Full information on genetic quality control procedures and association modeling are provided in the study references. 19,20…”

Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition

“…6 Finally, to quantify the proportion of variance that remains unexplained by the pathways together, we calculated and tested PRS for the whole genome excluding these 9 pathways. 6 Finally, to quantify the proportion of variance that remains unexplained by the pathways together, we calculated and tested PRS for the whole genome excluding these 9 pathways.…”

Genetic risk score modifies the effect of APOE on risk and age onset of Alzheimer's disease

“…19 Several recent studies further demonstrated the combined effect of APOE and risk-associated SNPs on AD risk. [20][21][22][23][24][25] This finding has important implications in inherited risk assessment of AD. However, the polygenic risk scores (PRSs) used to measure the cumulative effect of SNPs in these studies are difficult to apply at an individual subject level because they are not standardized to the general population.…”