Table 2.
Association of genome-wide significant WM- and BG-PVS risk loci with PVS burden across the lifespan (i-Share study, N = 1,748) and across ancestries (Nagahama study, N = 2,862)
| GWAS meta-analysis | i-Share (dichotomous) | i-Share (continuous) | Nagahama (dichotomous) | Nagahama (continuous) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | chr:position | EA/OA | Nearest gene(s) | OR (95% CI) | P value | β (SE) | P value | OR (95% CI) | P value | β (SE) | P value |
| PVS in white matter (WM-PVS) | |||||||||||
| rs6011998 | 20:45269867 | C/T | SLC13A3 | 1.26 (0.83–1.92) | 0.28 | 0.164 (0.04) | 4.20 × 10−05a | 1.69 (1.33–2.13) | 1.22 × 10−05a | 0.037 (0.008) | 6.21 × 10−07a |
| rs13079464 | 3:13822439 | C/G | WNT7A | 1.12 (0.91–1.40) | 0.29 | 0.014 (0.02) | 0.50 | 1.16 (0.97–1.40) | 0.11 | 0.015 (0.006) | 1.50 × 10−02 |
| rs2425884 | 20:45258292 | C/T | SLC13A3 | 1.18 (0.95–1.45) | 0.13 | 0.077 (0.02) | 2.98 × 10−04a | 1.29 (1.09–1.52) | 3.48 × 10−03 | 0.026 (0.005) | 1.77 × 10−06a |
| rs10817108 | 9:113658671 | A/G | LPAR1 | 0.90 (0.69–1.17) | 0.44 | 0.058 (0.03) | 2.23 × 10−02 | 1.18 (0.98–1.43) | 0.07 | 0.017 (0.006) | 4.10 × 10−03 |
| rs2425881 | 20:45255618 | A/G | SLC13A3 | 1.47 (1.03–2.01) | 1.40 × 10−02 | 0.063 (0.03) | 2.62 × 10−02 | 1.18 (1.01–1.37) | 3.66 × 10−02 | 0.014 (0.005) | 4.68 × 10−03 |
| rs3772833 | 3:124518362 | G/A | ITGB5, UMPS | 1.22 (0.89–1.66) | 0.21 | 0.006 (0.03) | 0.85 | 1.06 (0.88–1.29) | 0.51 | 0.008 (0.006) | 0.16 |
| rs112407396 | 20:45276381 | T/A | SLC13A3 | 1.47 (0.77–2.78) | 0.24 | 0.147 (0.07) | 3.13 × 10−02 | NA | NA | NA | NA |
| rs10494988 | 1:215141570 | C/T | CENPF, KCNK2 | 1.18 (0.95–1.47) | 0.14 | 0.079 (0.02) | 1.94 × 10−04a | 1.01 (0.86–1.18) | 0.90 | −0.002 (0.005) | 0.67 |
| rs72485816 | 20:45314435 | T/C | TP53RK, SLC13A3 | 1.01 (0.56–1.80) | 0.98 | 0.093 (0.06) | 0.095 | 1.32 (1.10–1.59) | 2.83 × 10−03 | 0.033 (0.006) | 1.91 × 10−08b |
| rs8041189 | 15:85686327 | G/A | PDE8A | 1.14 (0.89–1.44) | 0.30 | 0.041 (0.02) | 0.073 | 1.67 (0.84–3.33) | 0.14 | 0.046 (0.021) | 2.40 × 10−02 |
| rs4685022 | 3:13832611 | G/A | WNT7A | 1.12 (0.88–1.42) | 0.34 | 0.023 (0.02) | 0.31 | 1.15 (0.97–1.36) | 0.10 | 0.010 (0.005) | 0.075c |
| rs7596872 | 2:56128091 | C/A | EFEMP1 | 1.65 (1.10–2.46) | 1.14 × 10−02 | 0.089 (0.03) | 1.10 × 10−02 | NA | NA | NA | NA |
| rs1126642 | 17:42989063 | C/T | GFAP | 1.13 (0.65–1.97) | 0.67 | 0.127 (0.05) | 1.27 × 10−02 | 1.35 (1.09–1.67) | 0.11 | 0.033 (0.007) | 9.88 × 10−07a |
| rs687610 | 3:193515781 | G/C | OPA1 | 1.46 (1.18–1.80) | 4.88 × 10−04a | 0.109 (0.02) | 1.29 × 10−07a | 0.95 (0.81–1.13) | 0.59 | 0.006 (0.005) | 0.28 |
| rs4959689 | 6:2617122 | C/A | C6orf195 | 1.10 (0.89–1.37) | 0.37 | 0.022 (0.02) | 0.30 | NA | NA | 0.024 (0.026) | 0.34c |
| rs56104388 | 20:45302135 | T/C | SLC13A3 | 1.30 (0.40–4.24) | 0.67 | 0.274 (0.11) | 1.47 × 10−02 | NA | NA | NA | NA |
| rs12417836 | 11:70089700 | T/C | FADD, PPFIA1 | 0.99 (0.64–1.56) | 0.99 | 0.045 (0.04) | 0.29 | 0.87 (0.62–1.21) | 0.40 | −0.002 (0.011) | 0.84 |
| rs2923437 | 8:42425399 | A/C | SMIM19, CHRNB3, SLC20A2 | 0.98 (0.78–1.23) | 0.88 | 0.047 (0.02) | 2.60 × 10−02 | 1.11 (0.94–1.31) | 0.23 | 0.008 (0.005) | 0.11 |
| rs1922930 | 6:1364691 | C/A | FOXQ1, FOXF2 | 0.93 (0.65–1.33) | 0.70 | 0.035 (0.04) | 0.33 | NA | NA | NA | NA |
| rs2385089 | 19:18550434 | A/C | ISYNA1, ELL, LRRC25 | 1.20 (0.94–1.53) | 0.14 | 0.049 (0.03) | 0.057 | NA | NA | NA | NA |
| rs10954468 | 7:134434661 | C/A | BPGM, CALD1 | 1.08 (0.86–1.36) | 0.50 | 0.033 (0.02) | 0.13 | NA | NA | NA | NA |
| PVS in basal ganglia (BG-PVS) | |||||||||||
| rs4675310d | 2:203880834 | A/G | NBEAL1, ICA1L | 1.07 (0.81–1.41) | 0.61 | 0.01 (0.04) | 0.78 | 1.88 (0.63-5.60) | 0.26 | 0.046 (0.03) | 0.11 |
| rs6769442 | 3:171565463 | G/A | TMEM212 | 1.10 (0.87–1.40) | 0.37 | 0.03 (0.03) | 0.33 | 1.04 (0.71-1.53) | 0.82 | 0.008 (0.01) | 0.35 |
NA in the Nagahama Study correspond to variants that are rare (MAF < 1%: rs7596872; rs1922930; rs10954468) or monomorphic (rs112407396; rs56104388) in East Asians, or not available including in EAS 1000G data (rs2385089).
Analyses were adjusted for age, sex and intracranial volume, principal components of population stratification in the i-Share and Nagahama studies, and additionally adjusted for study center in the Nagahama study. In the Nagahama study, when the lead SNP from the PVS GWAS meta-analysis was not present, we used a tag SNP with r2 > 0.80 using the 1000G Japanese reference panel.
SNPs or tag SNPs (r² > 0.80, 1000G EAS) with a P < 0.05 are in bold.
aSNPs with a P < 1.09 × 10−3 (Bonferroni correction for 23 independent loci and two PVS locations).
bSNPs reaching genome-wide significance.
cThe tag SNP (r² > 0.80) is nominally significant: rs4685022 (r² = 0.81 with rs934448, 1000G EAS), P = 0.048; rs4959689 (r² = 0.83 with rs1772953, 1000G EAS), P = 0.02.
dThe lead SNP for this locus is not present in the Nagahama study; we used a tag SNP (rs150788469, r² = 1.0 with rs4675310) where the A allele of rs4675310 is in phase with the G allele of rs150788469.