Nature - 15.08.2019

Article reSeArcH

participants from three Finnish cohort studies: FINRISK^16 ,^17 partici-

pants not in FinMetSeq (n = 18,215), Northern Finland Birth Cohort

196618 (n = 5,139) and Helsinki Birth Cohort^19 (n = 1,412), all

imputed using the Finnish SISu v.2 reference panel (www.sisuproject.

fi). Following association analysis within each cohort, we conducted

a meta-analysis of the three imputation-based studies to test for rep-

lication of FinMetSeq variants (replication analysis) and a four-study

meta-analysis with FinMetSeq to follow up on suggestive associations

(combined analysis).

Of 448 significant variant–trait associations with replication data,

392 (87.5%) replicated at P < 0.05 (Supplementary Table 11). Of

the 1,417 sub-threshold associations, 431 reached P <  5  ×  10 −^7 in

the combined analysis (Supplementary Table 12); more than 60%

of the variants were absent from the reference panel and thus could

not be tested further.

Among the significant associations from FinMetSeq or the combined

analysis, 43  associations were with 2 6  predicted deleterious variants

(6 protein truncating variants (PTVs) and 20  missense variants) that

Table 1 | Associations with predicted deleterious variants from FinMetSeq or combined analysis

Chromosome:

position Gene

FinMetSeq

MAF NFE MAF MAF ratio (95% CI) Trait FinMetSeq P FinMetSeq β

Replication or

combined P

Replication or

combined β

1:55,076,137 FAM151A 0.099 0.0147 6.7 (6.1–7.5) IDL-C 5.4 ×  10 −^16 −0.187 2.1 ×  10 −^17 −0.191

IDL-P 8.9 ×  10 −^14 −0.172 1.9 ×  10 −^16 −0.185

2:120,848,049 EPB41L5 0.085 0.044 1.9 (1.8–2.1) eGFRa 1.7 ×  10 −^6 −0.093 4.8 ×  10 −^12 −0.107

Creatininea 2.5 ×  10 −^6 0.091 2.5 ×  10 −^12 0.098

3:125,831,672 ALDH1L1 0.0026 0 ∞ Gly 1.8 ×  10 −^8 −0.873 4.5 ×  10 −^4 −0.827

4:13,612,630 BOD1L1 0.0001 0 ∞ WHR 4.7 ×  10 −^7 −2.501 NA NA

5:79,336,091 THBS4 0.0045 0.0001 45 (14.4–140.9) Weighta 6.7 ×  10 −^7 −0.377 3.2 ×  10 −^7 −0.252

5:140,181,423 PCDHA3 0.0001 NA NA WHR 2.7 ×  10 −^7 2.559 NA NA

9:107,548,661 ABCA1 0.00023 0 ∞ HDL-C 4.8 ×  10 −^10 −2.046 NA NA

9:136,501,728 DBH 0.05 0.0021 23.8 (18.4–30.4) DBPa 1.5 ×  10 −^6 −0.115 2.8 ×  10 −^12 −0.11

11:47,282,929 NR1H3 0.0042 0.00003 140 (19.5–1004.4) HDL-C 1.4 ×  10 −^7 0.425 6.7 ×  10 −^7 0.435

HDL2-Ca 3.2 ×  10 −^6 0.473 1.3 ×  10 −^8 0.458

VLDL-Ca 4.0 ×  10 −^6 −0.469 3.1 ×  10 −^7 −0.412

11:116,692,293 APOA4 0.0096 0.012 0.8 (0.7–0.9) HDL-Ca 2.2 ×  10 −^5 0.225 1.5 ×  10 −^7 0.196

11:117,352,857 DSCAML1 0.016 0.0002 80 (35.7–179.3) VLDL-C 4.1 ×  10 −^8 0.299 2.0 ×  10 −^3 0.162

14:101,198,426 DLK1 0.023 0.00013 177 (66.3–472.4) Heighta 2.7 ×  10 −^5 −0.149 1.2 ×  10 −^10 −0.163

16:55,862,682 CES1 0.0018 0.00003 60 (8.3–432.0) HDL-C 1.1 ×  10 −^10 0.771 3.8 ×  10 −^6 0.793

ApoA1a 1.9 ×  10 −^6 0.668 4.0 ×  10 −^9 0.718

16:56,996,009 CETP 0.0017 0.00003 56.7 (7.9–408.3) ApoA1 2.6 ×  10 −^8 0.834 1.8 ×  10 −^4 1.034

HDL-C 1.1 ×  10 −^14 0.946 8.8 ×  10 −^21 1.217

16:68,013,570 DPEP3 0.0099 0.00044 22.5 (12.9–39.1) HDL-C 1.6 ×  10 −^7 −0.295 7.2 ×  10 −^15 −0.373

ApoA1a 5.2 ×  10 −^6 −0.294 4.0 ×  10 −^7 −0.253

16:68,732,169 CDH3 0.0044 0.00064 6.9 (4.2–11.2) Pyruvatea 3.7 ×  10 −^5 0.417 6.6 ×  10 −^10 0.471

17:6,599,157 SLC13A5 0.00091 0 ∞ Citrate 1.3 ×  10 −^9 1.294 9.5 ×  10 −^12 1.309

17:7,129,898 DVL2 0.02 0.02 1.0 (0.9–1.1) Vala 4.2 ×  10 −^5 −0.239 5.7 ×  10 −^9 −0.232

17:39,135,270 KRT40 0.00013 0 ∞ HDL-C 3.2 ×  10 −^8 2.416 NA NA

17:41,062,979 G6PC 0.025 0 ∞ MUFA 4.4 ×  10 −^7 0.275 3.5 ×  10 −^1 0.067

Glycerola 5.8 ×  10 −^6 0.218 4.1 ×  10 −^7 0.183

CRPa 1.6 ×  10 −^5 0.175 4.0 ×  10 −^9 0.185

Total TGa 1.0 ×  10 −^6 0.23 1.3 ×  10 −^7 0.197

17:41,926,216 CD300LG 0.00034 0 ∞ HDL-C 4.8 ×  10 −^14 2.061 4.9 ×  10 −^2 0.801

HDL2-C 1.3 ×  10 −^7 2.154 NA NA

ApoA1 8.1 ×  10 −^8 1.694 NA NA

18:47,091,686 LIPG 0.0025 0 ∞ HDL2-Ca 1.2 ×  10 −^5 0.579 5.6 ×  10 −^10 0.624

PCa 3.1 ×  10 −^6 0.624 1.1 ×  10 −^8 0.578

Total PGa 9.0 ×  10 −^6 0.594 1.1 ×  10 −^7 0.538

19:10,683,762 AP1M2 0.015 0.00009 167 (41.6–668.5) ApoB 5.8 ×  10 −^8 −0.282 1.5 ×  10 −^3 −0.199

IDL-Ca 1.1 ×  10 −^6 −0.289 6.9 ×  10 −^14 −0.319

IDL-Pa 2.1 ×  10 −^6 −0.281 8.5 ×  10 −^14 −0.318

Rem-

nant-Ca

8.0 ×  10 −^6 −0.268 2.7 ×  10 −^12 −0.301

19:11,350,904 ANGPTL8 0.0025 0 ∞ HDL2-Ca 3.4 ×  10 −^6 0.564 1.1 ×  10 −^8 0.574
19:49,318,380 HSD17B14 0.046 0.05 0.9 (0.8–1.0) Vala 3.4 ×  10 −^5 −0.152 2.1 ×  10 −^7 −0.144
20:24,994,201 ACSS1 0.0026 0 ∞ Acetatea 1.3 ×  10 −^5 0.626 2.1 ×  10 −^12 0.631
Chromosome positions were based on GRCh37. NFE MAFs were taken from gnomAD v.2.1 control exomes excluding Estonian or Swedish individuals. MAF: 0, variant present in gnomAD, but not in NFE
controls; NA, variant not present in gnomAD. Replication values with P < 0.05 are highlighted in bold. 95% CI, 95% confidence interval. See Supplementary Table 4 for trait abbreviations.
aAssociated traits that only reach significance in combined analysis.

15 AUGUSt 2019 | VOl 572 | NAtUre | 325