Table 1.

Genetic variants associated with high PVS burden

Region	SNP ALL	chr:position	EA/OA	EAF	Function	Nearest gene(s)	Effect (β)a	SEa	Z-scoreb	Dirb	N ext-PVS/N total	P value EUR	P value All	Het P value
PVS in white matter (WM-PVS)
20q13.12	rs6011998	20:45269867	C/T	0.95	intronic	SLC13A3	0.087	0.009	10.65	++++	9,502/39,128	1.90 × 10−24	1.80 × 10−26	0.11
3p25.1	rs13079464	3:13822439	C/G	0.46	intergenic	WNT7A	0.026	0.004	8.70	++++	9,614/39,822	8.64 × 10−17	3.41 × 10−18	0.59
20q13.12	rs2425884	20:45258292	C/T	0.57	intronic	SLC13A3	0.029	0.004	8.63	+−+−	9,614/39,822	2.60 × 10−18	6.02 × 10−18	0.14
9q31.3	rs10817108c	9:113658671	A/G	0.21	intronic	LPAR1	0.029	0.004	8.20	+++?	9,550/39,516	1.07 × 10−15	2.46 × 10−16	0.75
20q13.12	rs2425881	20:45255618	A/G	0.83	intronic	SLC13A3	0.033	0.005	7.68	+−+?	9,496/39,087	2.02 × 10−15	1.59 × 10−14	0.06
3q21.2	rs3772833	3:124518362	G/A	0.83	intronic	ITGB5, UMPS	0.032	0.005	7.67	+++?	9,496/39,087	2.15 × 10−13	1.76 × 10−14	0.39
20q13.12	rs112407396	20:45276381	T/A	0.03	intronic	SLC13A3	0.078	0.012	6.91	+???	8,426/34,530	4.81 × 10−12	4.81 × 10−12	1.00
1q41	rs10494988	1:215141570	C/T	0.63	intergenic	CENPF, KCNK2	0.021	0.004	6.54	++++	9,614/39,822	2.23 × 10−10	6.03 × 10−11	0.69
20q13.12	rs72485816d	20:45314435	T/C	0.96	UTR3	TP53RK, SLC13A3	0.059	0.010	6.45	++?−	9,114/37,342	1.47 × 10−10	1.12 × 10−10	0.87
15q25.3	rs8041189	15:85686327	G/A	0.70	intergenic	PDE8A	0.022	0.004	6.44	+−??	9,486/39,315	7.30 × 10−11	1.24 × 10−10	0.31
3p25	rs4685022	3:13832611	G/A	0.65	intergenic	WNT7A	0.019	0.004	6.40	+++?	9,576/39,654	2.36 × 10−09	1.58 × 10−10	0.11
2p16.1	rs7596872	2:56128091	C/A	0.90	intronic	EFEMP1	0.033	0.006	6.31	+−??	9,333/38,442	1.00 × 10−10	2.80 × 10−10	0.11
17q21.31	rs1126642	17:42989063	C/T	0.96	exonic	GFAP	0.051	0.009	6.23	+?+?	9,119/37,466	6.19 × 10−10	4.67 × 10−10	0.72
3q29	rs687610d	3:193515781	G/C	0.43	intergenic	OPA1	0.021	0.004	6.20	+++−	9,614/39,822	2.99 × 10−10	5.81 × 10−10	0.76
6p25.2	rs4959689	6:2617122	C/A	0.58	intergenic	C6orf195	0.020	0.004	6.03	++++	9,582/39,695	3.37 × 10−09	1.63 × 10−09	1.00
20q13.12	rs56104388	20:45302135	T/C	0.99	intronic	SLC13A3	0.101	0.017	5.85	+???	7,626/30,916	4.80 × 10−09	4.80 × 10−09	1.00
11q13.3	rs12417836	11:70089700	T/C	0.07	intergenic	FADD, PPFIA1	0.034	0.007	5.58	+−+?	9,464/38,960	1.56 × 10−08	2.47 × 10−08	0.40
8p11.21	rs2923437d	8:42425399	A/C	0.41	intergenic	SMIM19, CHRNB3, SLC20A2	0.018	0.004	5.49	++−−	9,614/39,822	4.73 × 10−08	4.08 × 10−08	0.14
6p25.3	rs1922930	6:1364691	C/A	0.12	intergenic	FOXQ1, FOXF2	0.029	0.006	5.47	++??	9,406/38,748	3.60 × 10−08	4.62 × 10−08	0.48
19p13.11	rs2385089	19:18550434	A/C	0.74	intergenic	ISYNA1, ELL, LRRC25c	0.023	0.005	5.49	+++−	9,614/39,822	4.14 × 10−08	5.73 × 10−08	0.57
7q33	rs10954468	7:134434661	C/A	0.40	intergenic	BPGM, CALD1c	0.019	0.004	5.52	+−?+	9,524/39,483	3.39 × 10−08	8.79 × 10−08	0.29
PVS in basal ganglia (BG-PVS)
2q33.2	rs4675310d	2:203880834	A/G	0.87	intronic	NBEAL1, ICA1L	0.027	0.005	5.92	++??	9,011/39,243	2.71 × 10−09	3.27 × 10−09	0.64
3q26.31	rs6769442	3:171565463	G/A	0.75	intronic	TMEM212	0.020	0.004	5.74	++?+	9,101/39,788	1.68 × 10−08	9.34 × 10−09	0.96
PVS in hippocampus (HIP-PVS)
1q25.3	rs10797812d	1:182984597	A/G	0.54	intergenic	SHCBP1L, LAMC1	0.027	0.004	7.84	++++	9,399/40,095	1.67 × 10−14	4.39 × 10−15	0.68
2p16.1	rs78857879d	2:56135099	G/A	0.90	intronic	EFEMP1	0.038	0.006	6.43	+???	9,033/38,008	8.20 × 10−11	1.31 × 10−10	1.00
1q41	rs6540873	1:215137222	A/C	0.62	intergenic	CENPF, KCNK2	0.020	0.004	5.95	+−−+	9,399/40,095	1.38 × 10−09	2.72 × 10−09	0.11

EA, effect allele; OA, other allele; EAF, effect allele frequency; Z-scores of the sample size-weighted cross-ancestry meta-analysis are represented, except for the two SNPs reaching genome-wide significance in Europeans only (rs2385089, rs10954468) for which the European meta-analysis Z-score is reported; dir, the association direction of the EA with the phenotype (extensive PVS burden versus the rest) for European, Hispanic, Asian and African-American ancestry studies, in this order; N ext-PVS, the number of participants with extensive PVS burden in the cross-ancestry meta-analysis, in each location (WM-PVS, BG-PVS, HIP-PVS); N total, the total number of participants in the cross-ancestry meta-analysis; P value EUR, P value in the European meta-analysis; P value All, P value in the cross-ancestry meta-analysis; Het P value corresponds to the heterogeneity P value in the meta-analysis (except for rs2385089 and rs10954468 for which the European meta-analysis Het P value is reported); P values for genome-wide significant loci (P < 5 × 10⁻⁸) are in bold; PVS GWAS analyses in individual cohorts were adjusted for age, sex and intracranial volume (or brain parenchymal fraction for ASPS), principal components of population stratification, and study site.

^aFrom cross-ancestry inverse variance-weighted meta-analysis.

^bFrom cross-ancestry Z-score-based meta-analysis.

^cGenome-wide significant association in Europeans only.

^dFor these loci, the lead SNP was different in the European meta-analysis (Cross-ancestry lead SNP → European lead SNP: rs72485816→rs6094423; rs687610→rs6444747; rs2923437→rs62509329; rs4675310→rs140244541; rs10797812→rs2022392; rs78857879→rs7596872); the P value corresponding to the European lead SNP is reported under "P value EUR" (r² > 0.50 between the European and cross-ancestry lead SNPs at these loci).