Alzheimer's disease, late-onset (IGAP)
Updated Genetics of Alzheimer's Disease
The below tables provide the best glimpse to date of the genetics of Alzheimer's disease. Tables (b) and on include results from the recent International Genomics of Alzheimer's Project which is the largest genetic study in AD yet.
(a) These are established AD SNPs.
| SNP | Gene | MAF | Major/Minor | OR * | PAF |
| rs4147929 | ABCA7 | 0.16 | G/A | 1.15 (1.11–1.19) | 2.8 |
| rs6733839 | BIN1 | 0.37 | C/T | 1.22 (1.18–1.25) | 8.1 |
| rs10948363 | CD2AP | 0.26 | A/G | 1.10 (1.07–1.13) | 2.3 |
| rs9331896 | CLU | 0.40 | T/C | 0.86 (0.84–0.89) | 5.3 |
| rs6656401 | CR1 | 0.19 | G/A | 1.18 (1.14–1.22) | 3.7 |
| rs11771145 | EPHA1 | 0.35 | G/A | 0.90 (0.88–0.93) | 3.1 |
| rs983392 | MS4A6A | 0.41 | A/G | 0.90 (0.87–0.92) | 4.2 |
| rs10792832 | PICALM | 0.37 | G/A | 0.87 (0.85–0.89) | 5.3 |
| rs429358 | ApoE-ε4 | 0.12 | T/C | 4.89 (4.45–5.39) | 27.3 |
| rs75932628 | TREM2 | 0.002 | C/T | 4.5 (1.7–11.9) | 0.8 |
| rs3865444 | CD33 | 0.238 | G/T | 0.89 (0.86,0.92) | -- |
- ORs (Odds Ratios) are relative to the minor allele
--(This established AD SNP was not confirmed in IGAP)
[Population attributable fraction (PAF)]
(b) These are newly confirmed AD SNPs in IGAP.
| SNP | Gene | MAF | Major/Minor | OR * | PAF |
| rs7274581 | CASS4 | 0.08 | T/C | 0.88 (0.84–0.92) | 1.1 |
| rs10838725 | CELF1 | 0.31 | T/C | 1.08 (1.05–1.11) | 2.4 |
| rs17125944 | FERMT2 | 0.08 | T/C | 1.14 (1.09–1.19) | 1.5 |
| rs9271192 | HLA | 0.28 | A/C | 1.11 (1.08–1.15) | 3.2 |
| rs35349669 | INPP5D | 0.46 | C/T | 1.08 (1.05–1.11) | 4.6 |
| rs190982 | MEF2C | 0.39 | A/G | 0.93 (0.90–0.95) | 2.7 |
| rs2718058 | NME8 | 0.37 | A/G | 0.93 (0.90–0.95) | 2.9 |
| rs28834970 | PTK2B | 0.36 | T/C | 1.10 (1.08–1.13) | 3.1 |
| rs10498633 | SLC24A4 | 0.21 | G/T | 0.91 (0.88–0.94) | 1.5 |
| rs11218343 | SORL1 | 0.04 | T/C | 0.77 (0.72–0.82) | 1.1 |
| rs1476679 | ZCWPW1 | 0.29 | T/C | 0.91 (0.89–0.94) | 3.2 |
| Total PAF | 61.8 |
- ORs (Odds Ratios) are relative to the minor allele
(c) TREML2 and TRIP4 were suggestive SNPs from IGAP that have now been confirmed AD SNPs.
| SNP | Gene | MAF | Major/Minor | OR * | P value |
| rs9381040 | TREML2 | 0.297 | C/T | 0.93 (0.91–0.96) | 1.30 ×10−6 SUG |
| rs74615166 | TRIP4 | 0.02 | T/C | 1.29 (1.17–1.42) | 9.74 ×10−9 SUG |
- ORs (Odds Ratios) are relative to the minor allele
(d) These are suggestive SNPs from IGAP that are yet to be confirmed.
| SNP | Gene | MAF | Major/Minor | OR * | P value |
| rs8035452 | SPPL2A | 0.339 | T/C | 0.93 (0.91–0.96) | 3× 10-7 SUG |
| rs7920721 | ECHDC3 | 0.387 | A/G | 1.07 (1.04–1.10) | 3× 10-7 SUG |
| rs7818382 | NDUFAF6 | 0.469 | C/T | 1.07 (1.04–1.10) | 8× 10-8 SUG |
| rs7295246 | ADAMTS20 | 0.406 | T/G | 1.07 (1.04–1.10) | 3× 10-7 SUG |
| rs7225151 | SCIMP | 0.121 | G/A | 1.10 (1.06–1.15) | 3× 10-7 SUG |
| rs6678275 | None | 0.169 | G/C | 1.09 (1.05–1.13) | 3× 10-7 SUG |
| rs6448799 | HS3ST1 | 0.300 | C/T | 1.08 (1.05–1.11) | 8× 10-8 SUG |
| rs72807343 | SQSTM1 | 0.011 | C/T | 1.35 (1.20-1.52) | 7× 10-7 SUG |
| rs2337406 | IGH | 0.178 | A/G | 1.15 (1.09-1.20) | 3× 10-7 SUG |
| (chr17:61538148 corresponds to chr17:63460787 on build 37 where below SNP is located) | |||||
| rs138190086 | ACE | 0.011 | A/G | 1.34 (1.20-1.50) | 3× 10-7 SUG |
| rs10751667 | AP2A2 | 0.439 | A/T | 1.07 (1.04-1.11) | 6× 10-7 SUG |
- ORs (Odds Ratios) are relative to the minor allele
(e)
| SNP | Gene | MAF | Major/Minor | OR * | P value |
| rs8093731 | DSG2 | 0.017 | C/T | 0.73 (0.62–0.86) | 3.02 × 10−5 |
- OR (Odds Ratio) is relative to minor allele
Note: It is not clear where this SNP from the second quoted study is obtained. This gene is not quoted on the commentary on the IGAP study.
(f) A new analysis of the IGAP dataset has revealed two new genes and three new variants involved in AD risk/protection.
| SNP | Gene | MAF | Major/Minor | OR * | P value |
| rs72824905 | PLCG2 | 0.0093 | C/G | 0.68 | 5.38 × 10−10 |
| rs616338 | ABI3 | 0.008 | C/T | 1.43 | 4.56 × 10−10 |
| rs143332484 | TREM2 | 0.0089 | C/T | 1.67 | 1.55 × 10−14 |
Tables a and b are modified from the article:
[PMID 24443964] Review: The genetics of Alzheimer's disease; putting flesh on the bones
Tables c, d, and e are modified from: [PMID 28714976] Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Tables f is from: [PMID 24495969] Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as novel susceptibility gene
TREML2 was confirmed as an AD gene in:
[PMID 24439484] Missense variant in TREML2 protects against Alzheimer's disease
Article found that rs3747742 G (minor allele) reduces AD risk
SPI1 gene makes the PU.1 transcription factor which has various roles related to immune function in AD. [PMID 28628103] A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease
TYROBP is another accepted AD gene involved with binding TREM2 [PMID 27658901] TYROBP genetic variants in early-onset Alzheimer's disease
Predictive pathological control AUC of 84%. Clinically relevant predictive ability [PMID 28727176] Polygenic Risk Score Analysis of Pathologically Confirmed Alzheimer's Disease
