Table 2.
Novel genome-wide significant loci in European-only analysis
| European Discovery | Multi-ancestry discovery | 23andMe European replication (N = 2,904,664) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Variant | Chr:position | Alleles (EAF) | OR (CI) | P | N (studies) | P | N (studies) | OR (CI) | P | Gene | Pathway |
| rs301804b | 1:8476441 | G/C (0.30) | 1.05 (1.03–1.07) | 2.3E−09 | 698266 (39) | 8.5E−09 | 707642 (43) | 1.03 (1.02–1.03) | 5.5E−16 | RERE | Apoptosis |
| rs61776548 | 1:12091024 | A/G (0.47) | 1.04 (1.02–1.05) | 4.2E−08 | 787144 (39) | 1.4E−07 | 1008560 (44) | 1.02 (1.01–1.02) | 5.6E−09 | TNFRSF1B | Cytokine signalling in immune response |
| rs12565349 | 1:110371629 | G/C (0.15) | 1.05 (1.03–1.07) | 1.3E−08 | 862259 (39) | 1.9E−07 | 1083670 (44) | 1.03 (1.02–1.04) | 5.8E−15 | CSF1 | Cytokine signalling in immune response |
| rs187080438 | 1:150374354 | T/C (0.03) | 1.17 (1.11–1.23) | 3.7E−10 | 758729 (20) | 2.2E−12 | 765209 (22) | 1.14 (1.12–1.16) | 2.0E−41 | CTSS | Antigen presentation in immune response |
| rs146527530b | 1:151059196 | G/T (0.02) | 1.27 (1.20–1.35) | 5.5E−15 | 744128 (13) | 7.4E−19 | 744128 (13) | 1.25 (1.22–1.28) | 1.5E−88 | CTSS | Antigen presentation in immune response |
| rs115161931b | 1:151063299 | T/C (0.04) | 1.18 (1.13–1.23) | 1.0E−13 | 472565 (26) | 3.2E−12 | 479045 (28) | 1.09 (1.08–1.11) | 2.0E−32 | CTSS | Antigen presentation in immune response |
| rs71625130b | 1:151625094 | A/G (0.04) | 1.23 (1.18–1.28) | 2.4E−27 | 770827 (25) | 7.2E−30 | 772963 (26) | 1.17 (1.16–1.19) | 1.7E−89 | RORCc | Cytokine signalling in immune response |
| rs149199808b | 1:151626396 | T/C (0.03) | 1.32 (1.26-1.38) | 4.4E−30 | 756174 (19) | 8.7E−34 | 762654 (21) | 1.24 (1.22–1.26) | 3.1E−134 | RORC | Cytokine signalling in immune response |
| rs821429b | 1:153275443 | A/G (0.96) | 0.86 (0.84–0.89) | 5.9E−18 | 852224 (30) | 8.2E−16 | 858704 (32) | 0.91 (0.89–0.92) | 2.7E−38 | S100A7 | Differentiation regulation incl. in the innate immune system |
| rs12138773 | 1:153843489 | A/C (0.03) | 1.11 (1.07–1.16) | 2.3E−08 | 851937 (28) | 1.3E−09 | 858417 (30) | 1.07 (1.05–1.09) | 3.5E−16 | S100A12c | Regulation of inflammatory processes and immune response |
| rs67766926a,b | 2:61163581 | G/C (0.23) | 1.05 (1.03–1.06) | 5.7E−10 | 863063 (39) | 2.9E−11 | 1084480 (44) | 1.05 (1.04–1.05) | 1.2E−41 | AHSA2P | Protein folding |
| rs112385344 | 2:112275538 | T/C (0.12) | 1.06 (1.04–1.08) | 2.8E−09 | 852837 (34) | 3.9E−08 | 862213 (38) | 1.04 (1.03–1.05) | 1.5E−18 | MERTKc | Inhibits TLR-mediated innate immune response |
| rs62193132 | 2:242788256 | T/C (0.46) | 1.04 (1.03–1.06) | 1.5E−09 | 832761 (26) | 7.1E−08 | 1052040 (30) | 1.03 (1.02–1.03) | 1.5E−19 | NEU4 | Sphingolipid metabolism |
| rs10833b | 4:142654547 | C/T (0.65) | 1.04 (1.03–1.06) | 7.3E−09 | 859747 (38) | 6.0E−08 | 1081160 (43) | 1.02 (1.02–1.03) | 3.4E−15 | IL15 | Cytokine signalling in immune response |
| rs148161264b | 5:14604521 | G/C (0.04) | 1.10 (1.07–1.14) | 7.4E−10 | 850619 (29) | 2.0E−08 | 857099 (31) | 1.05 (1.03–1.06) | 1.6E−08 | OTULINL | Endoplasmic reticulum component |
| rs7701967 | 5:130059750 | A/G (0.31) | 0.95 (0.94–0.97) | 3.4E−09 | 520344 (36) | 3.6E−09 | 529720 (40) | 0.99 (0.98–0.99) | 1.1E−06 | LYRM7 | Mitochondrial respiratory chain complex assembly |
| rs4532376b | 5:176774403 | A/G (0.30) | 1.04 (1.03–1.06) | 3.5E−09 | 859747 (38) | 2.3E−09 | 1081160 (43) | 1.03 (1.02–1.03) | 1.4E−18 | RGS14 | G-alpha signalling |
| rs72925996b | 6:90930513 | C/T (0.33) | 0.96 (0.94–0.97) | 3.2E−10 | 862259 (39) | 5.4E−09 | 1083670 (44) | 0.96 (0.95–0.96) | 2.2E−44 | BACH2 | NF-kappaB proinflammatory signalling |
| rs989437 | 7:28830498 | G/A (0.61) | 0.96 (0.95–0.97) | 6.1E−11 | 864982 (40) | 1.0E−09 | 1086390 (45) | 0.97 (0.96–0.97) | 6.9E−31 | CREB5c | AMPK & ATK signalling |
| rs34215892 | 8:21767240 | A/G (0.03) | 0.87 (0.83–0.90) | 4.7E−11 | 436369 (24) | 2.0E−09 | 442849 (26) | 0.89 (0.88–0.91) | 1.0E−36 | DOK2 | Immune response IL-23 signalling |
| rs118162691 | 8:21767809 | A/C (0.05) | 0.92 (0.89–0.94) | 7.8E−09 | 856229 (30) | 1.8E−07 | 862709 (32) | 0.90 (0.88–0.91) | 1.1E−44 | DOK2 | Immune response IL-23 signalling |
| rs7843258 | 8:141601542 | C/T (0.82) | 1.05 (1.04–1.07) | 1.5E−09 | 859747 (38) | 3.6E−10 | 1081160 (43) | 1.04 (1.03–1.05) | 7.0E−25 | AGO2 | siRNA-mediated gene silencing |
| rs7857407 | 9:33430707 | A/T (0.40) | 1.04 (1.02–1.05) | 2.5E−08 | 864982 (40) | 9.0E−09 | 1086390 (45) | 1.03 (1.02–1.03) | 5.1E−18 | AQP3 | Aquaporin-mediated transport |
| rs10988863 | 9:102331281 | C/A (0.21) | 0.95 (0.93–0.96) | 5.1E−11 | 862259 (39) | 3.0E−09 | 1083670 (44) | 0.97 (0.97–0.98) | 1.3E−13 | NR4A3 | Transcriptional activator |
| rs17368814 | 11:102748695 | G/A (0.13) | 0.95 (0.93–0.97) | 1.4E−08 | 858117 (37) | 6.8E−07 | 1078260 (41) | 0.95 (0.95–0.96) | 1.2E−27 | MMP12 | Extracellular matrix organisation |
| rs11216206 | 11:116843425 | G/C (0.07) | 1.10 (1.07–1.14) | 5.5E−10 | 557183 (35) | 2.9E−10 | 778595 (40) | 1.04 (1.03–1.05) | 8.5E−15 | SIK3 | LKB1 signalling |
| rs5005507b | 12:94611908 | C/G (0.74) | 1.05 (1.03–1.06) | 3.6E−09 | 859747 (38) | 9.6E−08 | 1081160 (43) | 1.03 (1.02–1.04) | 2.7E−18 | PLXNC1 | Semaphorin interactions incl. in immune response |
| rs7147439 | 14:105523663 | A/G (0.73) | 0.96 (0.95–0.97) | 4.7E−08 | 781909 (37) | 6.6E−07 | 1003320 (42) | 0.97 (0.96–0.97) | 4.8E−24 | GPR132 | GPCR signalling |
| rs2542147 | 18:12775851 | T/G (0.84) | 0.95 (0.93–0.96) | 1.5E−09 | 862470 (39) | 7.5E−08 | 1083880 (44) | 0.96 (0.95–0.97) | 2.6E−26 | PTPN2 | Cytokine signalling in immune response |
The lead SNP at each independent locus is displayed, along with the results from the European-only discovery, multi-ancestry discovery and European replication. The top-ranked gene from our gene prioritisation is listed, along with a description of the pathway/function of the gene. The evidence implicating each gene is presented in Supplementary Data 11.
Alleles are listed as Effect allele/other allele, the effect allele frequency (EAF) in Europeans (average EAF, weighted by the sample size of each cohort).
Genome build = GRCh37/hg19.
ars4643526 at the same locus was previously identified in the discovery analysis of Paternoster et al. 2. However, this association did not replicate in that study.
bWhilst not identified in any GWAS AD papers, these loci have previously shown evidence for association with AD in supplementary material of methodological papers92,93.
cOne of two or three tied genes at these loci are shown.