Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation ...in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.
We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped ...Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10−16, at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10−21). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10−16). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.
Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (
) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation ...in
with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in
that have a large effect on LDL cholesterol levels.
We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes.
We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of
in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL;
=8.4×10
). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of
. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (
=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (
=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers.
Del2.5 is the first reported gain-of-function mutation in
causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of
mRNA as a potent regulator of LDL receptor expression in humans.
Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment ...response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects.
We performed genome-wide association studies of serum levels of AFP (
= 22,686), carcinoembryonic antigen (
= 22,309), cancer antigens 15.3 (
= 7,107), 19.9 (
= 9,945), and 125 (
= 9,824), and ALP (
= 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry.
We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels.
Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood.
Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.
Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through ...whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in
(R436H) associating with lower levels of total cholesterol (effect = -0.47 standard deviations or -0.55 mmol L
,
= 4.21 × 10
,
= 150,211). Importantly,
R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease.
encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.
Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.
We sequenced the genomes of 2636 ...Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.
We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)).
ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).
Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. ...Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 rs17632542 (KLK3: I179T), each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary ...atherosclerosis.
To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis.
This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait.
Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides.
The extent of angiographic CAD and coronary artery calcium quantity.
A total of 12 460 adults (mean SD age, 65.1 10.7 years; 8383 men 67.3%) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL to convert to millimoles per liter, multiply by 0.0259) was associated with greater odds of obstructive CAD (odds ratio OR, 1.83 95% CI, 1.63-2.07; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 95% CI, 1.11-1.44; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 95% CI, 1.26-1.72; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 95% CI, 1.70-2.44; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 95% CI, 0.53-0.87; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol.
In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.
Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. ...Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
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