Explore the vast range of titles available.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4 , encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence ( P =1.2 × 10 −4 ). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer (LC; P =4.0 × 10 −4 ), chronic obstructive pulmonary disease (COPD; P =9.3 × 10 −4 ), peripheral artery disease (PAD; P =0.090) and abdominal aortic aneurysms (AAAs; P =0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P =2.2 × 10 −4 ), COPD (OR=3.22, P =2.9 × 10 −4 ), PAD (OR=3.47, P =9.2 × 10 −3 ) and AAA (OR=6.44, P =6.3 × 10 −3 ). Joint analysis of the four smoking-related diseases reveals significant association ( P =6.8 × 10 −5 ), particularly for early-onset cases ( P =2.1 × 10 −7 ). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Background:Germline CDKN2A mutations have been observed in 20–40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls.Methods:We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly.Results:We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma.Conclusions:This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.

In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

Gudmar Thorleifsson and colleagues report results of a large-scale genome-wide association and replication study for obesity-related traits. The newly discovered loci are enriched for genes expressed in the central nervous system, and may thus contribute to weight gain by modulating food intake. Similar results are reported in a related study by Joel Hirschhorn and colleagues. Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 × 10 −7 . This includes previously identified variants close to or in the FTO , MC4R , BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.

Gudbjartsson et al . report that variants near two genes, ASIP and TYR , are associated with risk of cutaneous melanoma and basal cell carcinoma. These loci are among several loci initially discovered for their role in human pigmentation, as reported by Sulem et al . In a separate study, Brown et al . independently discover an association between variants near ASIP and melanoma risk. Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP , known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 × 10 −9 ) and BCC (OR = 1.35, P = 1.2 × 10 −6 ). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 × 10 −7 ) and BCC (OR = 1.14, P = 6.1 × 10 −4 ). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.3 × 10 −4 ). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.

In the debate on biobank regulation, arguments often draw upon findings in surveys on public attitudes. However, surveys on willingness to participate in research may not always predict actual participation rates. We compared hypothetical willingness as estimated in 11 surveys conducted in Sweden, Iceland, United Kingdom, Ireland, United States and Singapore to factual participation rates in 12 biobank studies. Studies were matched by country and approximate time frame. Of 22 pairwise comparisons, 12 suggest that factual willingness to participate in biobank research is greater than hypothetical, six indicate the converse relationship, and four are inconclusive. Factual donors, in particular when recruited in health care or otherwise face-to-face with the researcher, are possibly motivated by factors that are less influential in a hypothetical context, such as altruism, trust, and sense of duty. The value of surveys in assessing factual willingness may thus be limited.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 × 10 −12 for rs10941679). The nearest gene, MRPS30 , was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.