Table 1 Loss-of-function variants associated with liver-related blood traits.

From: Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Gene variant

Chr:pos

Minor/major allele

rs ID

MAF % (MAC)

Rsq

Trait

N

Beta SD

SE

P

Discovery method

Novelty of variant-trait association

APOB p.K1813X

2:21011431

A/T

–

0.009 (10)

–

LDL-C

56815

−2.63

0.35

1.1 × 10−13

Custom array – predicted nonsense

Novel (in known LDL-C locus; known gene17,18)

APOB p.R1333X

2:21013379

A/G

rs121918383

0.009 (10)

–

LDL-C

55383

−2.80

0.35

2.5 × 10−15

Custom array – predicted nonsense

Novel (in known LDL-C locus; known gene17,18, variant previously linked to familial hypobetalipoproteinemia53)

APOB p.W3087X

2:21007608

T/C

rs745457003

0.011 (12)

–

LDL-C

55383

−2.79

0.32

5.1 × 10−18

Custom array – predicted nonsense

Novel (in known LDL-C locus; known gene17,18)

GPLD1 p.V815Sfs*46

6:24429112

C/CT

rs573778305

0.85

0.97

ALP

48578

−0.87

0.039

2.2 × 10−107

HUNT locus index variant (imputed from TOPMed)

Novel (in known ALP locus14; gene experimentally linked to liver disease54)

HBB p.Q40X

11:5226774

A/G

rs11549407

4.81

–

TC

5937

−0.48

0.048

5.4 × 10−23

Trans-ancestry meta-analysis index variant

Known (previously associated with beta thalassemia15, which again is known to be associated with decreased TC55)

LIPC p.G247Afs*11

15:58545904

ACG/A

rs749932377

0.16 (221)

0.88

HDL-C

69214

0.58

0.081

1.1 × 10−9

HUNT conditional analysis (imputed from TOPMed)

Novel (in known HDL-C locus;17,18 variant report in carrier with mixed hyperlipidemia but who also carried APOB variants56)

LPL p.S474X

8:19962213

G/C

rs328

11.9

1.00

TG

180981

−0.17

0.0057

1.3 × 10−196

Trans-ancestry meta-analysis index variant

Known variant at known locus17,18, experimentally shown to result in gain-of-function of LPL19.

SLC22A1 p.D426Pfs*28

6:160139865

C/CTGGTAAGT

rs113569197

39.3

0.99

LDL-C

67429

−0.05

0.0060

3.3 × 10−9

HUNT conditional analysis (imputed from TOPMed)

Novel (in known LDL-C locus17,18)

ZNF529 p.K405X

19:36547291

A/T

rs1376217616

0.099 (110)

–

LDL-C

55383

−0.60

0.11

1.3 × 10−8

Custom array – observed in low-pass genomes

Novel

  1. Reported allele frequencies are based on the HUNT population except for HBB p.Q40X which was based on the SardiNIA dataset since it was only present there.
  2. Chr Chromosome, pos position human genome build hg38, MAF Minor allele frequency, MAC minor allele count, Rsq imputation r2 in HUNT, SD standard deviation, SE standard error of the beta, P P value, LDL-C Low-density lipoprotein cholesterol, ALP Alkaline phosphatase, TC Total cholesterol, HDL-C High-density lipoprotein cholesterol, TG Triglyceride.
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