Genomic prediction of alcohol-related morbidity and mortality

While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85-12.58 g, p = 2.3 x 10(-58)). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66-2.01, p = 1.6 x 10(-36)). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26-1.99, p = 8.2 x 10(-5)). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20-1.47, p = 4.5 x 10(-8)) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes

Informed consent procedures in patients with an acute inability to provide informed consent : Policy and practice in the CENTER-TBI study

Purpose: Enrolling traumatic brain injury (731) patients with an inability to provide informed consent in research is challenging. Alternatives to patient consent are not sufficiently embedded in European and national legislation, which allows procedural variation and bias. We aimed to quantify variations in informed consent policy and practice. Methods: Variation was explored in the CENTER-TBI study. Policies were reported by using a questionnaire and national legislation. Data on used informed consent procedures were available for 4498 patients from 57 centres across 17 European countries. Results: Variation in the use of informed consent procedures was found between and within EU member states. Proxy informed consent (N = 1377;64%) was the most frequently used type of consent in the ICU, followed by patient informed consent (N 426;20%) and deferred consent (N 334;16%). Deferred consent was only actively used in 15 centres (26%), although it was considered valid in 47 centres (82%). Conclusions: Alternatives to patient consent are essential for TBI research. While there seems to be concordance amongst national legislations, there is regional variability in institutional practices with respect to the use of different informed consent procedures. Variation could be caused by several reasons, including inconsistencies in clear legislation or knowledge of such legislation amongst researchers. (C) 2020 Published by Elsevier Inc.Peer reviewe

Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration : Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report

Objective: Lipoprotein(a) (Lp[a]) is associated with coronary artery disease (CAD) but also to LDL (low-density lipoprotein) cholesterol. The genetic architecture of Lp(a) remains incompletely understood, as well as its independence of LDL cholesterol in its association to CAD. We investigated the genetic determinants of Lp(a) concentrations in a large prospective multiethnic cohort. We tested the association for potential causality between genetically determined higher Lp(a) concentrations and CAD using a multivariable Mendelian randomization strategy. Approach and Results: We studied 371 212 participants of the UK Biobank with available Lp(a) and genome-wide genetic data. Genome-wide association analyses confirmed 2 known and identified 37 novel loci (P Conclusions: This study supports an LDL cholesterol-independent causal link between Lp(a) and CAD. A rare missense variant in the LPA gene locus appears to be protective in people with the Lp(a) increasing variant of rs10455872. In the search for therapeutic targets of Lp(a), future work should focus on understanding the functional consequences of this missense variant.Peer reviewe

Neuregulin signaling pathway in smoking behavior

Peer reviewe

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

The role of polygenic risk and susceptibility genes in breast cancer over the course of life

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10-90(th) percentile) have a lifetime risk of breast cancer at 55% (95% CI 49-61%), which increases to 84% (71-97%) with a high PRS (>90(th) percentile), and decreases to 49% (30-68%) with a low PRS (<10(th) percentile). Similarly, for c.1100delC in CHEK2 (3.7-fold enrichment; 1648 carriers), the respective lifetime risks are 29% (27-32%), 59% (52-66%), and 9% (5-14%). The PRS also refines the risk assessment of women with first-degree relatives diagnosed with breast cancer, particularly among women with positive family history of early-onset breast cancer. Here we demonstrate the opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members. Identifying women at high risk of breast cancer has important implications for screening. Here, the authors demonstrate that polygenic risk scores improve breast cancer risk prediction in the population, in women with mutations in high-risk genes and in women with close relatives with the disease