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Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these ∼7500 persons, a common haplotype in the CHRNA3–CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P =6.9 × 10 −5 ). In a third set of European populations ( n =∼7500) which had been genotyped for ∼6000 SNPs in ∼2000 genes, an allele in the same haplotype was associated with CPD (nominal P =2.6 × 10 −6 ). These results (in three independent populations of European origin, totaling ∼15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.

Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.

Background: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. Methods: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. Results: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 ( UGT1A1 ) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study ( P <0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 × upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (⩾1.5 × ULN), 32 (84%) were either TA7 homozygotes ( n =18) or TA7 heterozygotes ( n =14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3–32.2) compared with other genotypes. Conclusions: The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

Aims/hypothesis Several susceptibility genes for type 2 diabetes have been discovered recently. Individually, these genes increase the disease risk only minimally. The goals of the present study were to determine, at the population level, the risk of diabetes in individuals who carry risk alleles within several susceptibility genes for the disease and the added value of this genetic information over the clinical predictors. Methods We constructed an additive genetic score using the most replicated single-nucleotide polymorphisms (SNPs) within 15 type 2 diabetes-susceptibility genes, weighting each SNP with its reported effect. We tested this score in the extensively phenotyped population-based cross-sectional CoLaus Study in Lausanne, Switzerland (n = 5,360), involving 356 diabetic individuals. Results The clinical predictors of prevalent diabetes were age, BMI, family history of diabetes, WHR, and triacylglycerol/HDL-cholesterol ratio. After adjustment for these variables, the risk of diabetes was 2.7 (95% CI 1.8-4.0, p = 0.000006) for individuals with a genetic score within the top quintile, compared with the bottom quintile. Adding the genetic score to the clinical covariates improved the area under the receiver operating characteristic curve slightly (from 0.86 to 0.87), yet significantly (p = 0.002). BMI was similar in these two extreme quintiles. Conclusions/interpretation In this population, a simple weighted 15 SNP-based genetic score provides additional information over clinical predictors of prevalent diabetes. At this stage, however, the clinical benefit of this genetic information is limited.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.

Elevated plasma levels of lipoprotein-associated phospholipase A 2 (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P =0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10 000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.

Background and objectives: Vitamin+mineral supplement (VMS) and dietary supplement (DS) use is widespread in the general population, but the motivations for such use are poorly known. The prevalence and characteristics of VMS and DS users in Lausanne, Switzerland, were thus assessed. Method: Cross-sectional study was performed including 3249 women and 2937 men (CoLaus study). VMS were defined as single or multivitamin-multimineral preparations. DS included omega-3 or omega-6 fatty acids, herbal teas, plant or animal extracts and bacterial (Lactobacillus) preparations. Calcium and iron supplements were assessed separately. Results: Twenty-six percent of the subjects reported using VMS or DS. VMS were the most frequently consumed item (16.8%), followed by DS (10%), calcium (6.6%) and iron (1.8%). Women reported a higher consumption than men. In women, VMS, DS and calcium use increased and iron use decreased with age, whereas in men only VMS and calcium intake increased with age. Multivariate analysis showed female gender, being born in Switzerland, increased age, higher education and increased physical activity to be positively related with VMS and DS. On bivariate analysis, VMS and DS users presented more frequently with arthritis, anxiety, depression and osteoporosis, but on multivariate analysis only positive relationships between DS use and anxiety/depression (odds ratio (OR)=1.40; 95% confidence interval (CI): [1.16-1.70]) and calcium and osteoporosis (OR=10.6; 95% CI [7.77-14.4]) were found. Conclusion: VMS and DS use is common in the population of Lausanne and associated with a better health profile. Calcium supplements are taken to prevent osteoporosis, whereas the rationale for taking other VMS and DS is unclear.

Several studies have reported high levels of inflammatory biomarkers in hypertension, but data coming from the general population are sparse, and sex differences have been little explored. The CoLaus Study is a cross-sectional examination survey in a random sample of 6067 Caucasians aged 35–75 years in Lausanne, Switzerland. Blood pressure (BP) was assessed using a validated oscillometric device. Anthropometric parameters were also measured, including body composition, using electrical bioimpedance. Crude serum levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and ultrasensitive C-reactive protein (hsCRP) were positively and IL-1β (IL-1β) negatively ( P <0.001 for all values), associated with BP. For IL-6, IL-1β and TNF-α, the association disappeared in multivariable analysis, largely explained by differences in age and body mass index, in particular fat mass. On the contrary, hsCRP remained independently and positively associated with systolic (β (95% confidence interval): 1.15 (0.64; 1.65); P <0.001) and diastolic (0.75 (0.42; 1.08); P <0.001) BP. Relationships of hsCRP, IL-6 and TNF-α with BP tended to be stronger in women than in men, partly related to the difference in fat mass, yet the interaction between sex and IL-6 persisted after correction for all tested confounders. In the general population, the associations between inflammatory biomarkers and rising levels of BP are mainly driven by age and fat mass. The stronger associations in women suggest that sex differences might exist in the complex interplay between BP and inflammation.

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P  = 7 × 10 −8 ), hospitalization (OR = 0.61, P  = 8 × 10 −8 ) and susceptibility (OR = 0.78, P  = 8 × 10 −6 ). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.

We have generated mice with markedly elevated plasma levels of human low density lipoprotein (LDL) and reduced plasma levels of high density lipoprotein. These mice have no functional LDL receptors [LDLR-/-] and express a human apolipoprotein B-100 (apoB) transgene [Tg(apoB+/+)] with or without an apo(a) transgene [Tg(apoa+/-)]. Twenty animals (10 males and 10 females) of each of the following four genotypes were maintained on a chow diet: (i) LDLR-/-, (ii) LDLR-/-;Tg(apoa+/-), (iii) LDLR-/-;Tg(apoB+/+), and (iv)LDLR-/-;Tg(apoB+/+);Tg(apo+/-). The mice were killed at 6 mo, and the percent area of the aortic intimal surface that stained positive for neutral lipid was quantified. Mean percent areas of lipid staining were not significantly different between the LDLR-/- and LDLR-/-;Tg(apoa+/-) mice (1.0 +/- 0.2% vs. 1.4 +/- 0.3%). However, the LDLR-/-;Tg(apoB+/+) mice had approximately 15-fold greater mean lesion area than the LDLR-/- mice. No significant difference was found in percent lesion area in the LDLR-/-;Tg(apoB+/+) mice whether or not they expressed apo(a) [18.5 +/- 2.5%, without lipoprotein(a), Lp(a), vs. 16.0 +/- 1.7%, with Lp(a)]. Histochemical analyses of the sections from the proximal aorta of LDLR-/-;Tg(apoB+/+) mice revealed large, complex, lipid-laden atherosclerotic lesions that stained intensely with human apoB-100 antibodies. In mice expressing Lp(a), large amounts of apo(a) protein colocalized with apoB-100 in the lesions. We conclude that LDLR-/-;Tg(apoB+/+) mice exhibit accelerated atherosclerosis on a chow diet and thus provide an excellent animal model in which to study atherosclerosis. We found no evidence that apo(a) increased atherosclerosis in this animal model