Multivariate linear regression adjusting for age, alcohol intake, smoking, BMI and vitamin D on each POP individually or the sum of OCP, PCB, OCP+PCB and PBDE.

<p>Multivariate linear regression adjusting for age, alcohol intake, smoking, BMI and vitamin D on each POP individually or the sum of OCP, PCB, OCP+PCB and PBDE.</p

Characteristics of the participants in the survey, based on intake of Greenlandic diet.

<p>Characteristics of the participants in the survey, based on intake of Greenlandic diet.</p

Serum concentrations (μg/kg lipid) of selected polychlorinated biphenyls (PCBs) among participants in the study.

<p>Serum concentrations (μg/kg lipid) of selected polychlorinated biphenyls (PCBs) among participants in the study.</p

Serum concentrations (μg/kg lipid) of summed organochlorine pesticides (ΣOCP), summed polychlorinated biphenyls ΣPCB), summed polybrominated diphenyl ethers (ΣPBDE) and summed OCP + summed PCB (ΣOCP+ΣPCB) among participants in the study.

<p>Serum concentrations (μg/kg lipid) of summed organochlorine pesticides (ΣOCP), summed polychlorinated biphenyls ΣPCB), summed polybrominated diphenyl ethers (ΣPBDE) and summed OCP + summed PCB (ΣOCP+ΣPCB) among participants in the study.</p

Serum concentrations (μg/kg lipid) of selected organochlorine pesticides (OCPs) among participants in the study.

<p>Serum concentrations (μg/kg lipid) of selected organochlorine pesticides (OCPs) among participants in the study.</p

The association between intake of Greenlandic food items and OCPs (top panel), PCBs (middle panel) and PBDEs (bottom panel).

<p>Median levels are shown with the 25^th and 75^th percentiles. P-value is for trend.</p

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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)). CONCLUSIONS: 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.)

Rare and low-frequency coding variants alter human adult heigh

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways