Methods and results from the genome-wide association group at GAW20

Background: This paper summarizes the contributions from the Genome-wide Association Study group (GWAS group) of the GAW20. The GWAS group contributions focused on topics such as association tests, phenotype imputation, and application of empirical kinships. The goals of the GWAS group contributions were varied. A real or a simulated data set based on the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study was employed by different methods. Different outcomes and covariates were considered, and quality control procedures varied throughout the contributions. Results: The consideration of heritability and family structure played a major role in some contributions. The inclusion of family information and adaptive weights based on data were found to improve power in genome-wide association studies. It was proven that gene-level approaches are more powerful than single-marker analysis. Other contributions focused on the comparison between pedigree-based kinship and empirical kinship matrices, and investigated similar results in heritability estimation, association mapping, and genomic prediction. A new approach for linkage mapping of triglyceride levels was able to identify a novel linkage signal. Conclusions: This summary paper reports on promising statistical approaches and findings of the members of the GWAS group applied on real and simulated data which encompass the current topics of epigenetic and pharmacogenomics

Identification of circulating lncRNAs associated with gallbladder cancer risk by tissue-based preselection, cis-eQTL validation, and analysis of association with genotype-based expression

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candi dates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on ex pression changes along the sequence “gallstones → dysplasia → GBC”. In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncR NAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associ ated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04–1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk

Gallstones, cholecystectomy and kidney cancer: observational and Mendelian randomisation results based on large cohorts.

BACKGROUND AND AIMS Gallstones (cholelithiasis) constitute a major health burden with high costs related to surgical removal of the gallbladder (cholecystectomy), generally indicated for symptomatic gallstones. The association between gallstones, cholecystectomy and kidney cancer is controversial. We comprehensively investigated this association, considering age at cholecystectomy and time from cholecystectomy to kidney cancer diagnosis, and assessing the causal effect of gallstones on kidney cancer risk by Mendelian randomisation (MR). METHODS We compared the risk of kidney cancer in cholecystectomised and non-cholecystectomised individuals (16.6 million in total) from the Swedish nationwide cancer, census, patient and death registries using hazard ratios (HRs). For two-sample and multivariable MR, we used summary statistics based on 408,567 UK Biobank participants. RESULTS During a median follow-up of 13 years, 2,627 of 627,870 cholecystectomised Swedish patients developed kidney cancer (HR=1.17, 95% CI 1.12-1.22). Kidney cancer risk was particularly increased in the first 6 months after cholecystectomy (HR=3.79, 95% CI 3.18-4.52) and in patients cholecystectomised before age 40 (HR=1.55, 95% CI 1.39-1.72). MR results based on 18.417 gallstone and 1,788 kidney cancer patients from the UK revealed a causal effect of gallstones on kidney cancer risk (9.6% risk increase per doubling in gallstone prevalence, 95% CI 1.2%-18.8%). CONCLUSIONS Both observational and causal MR estimates based on large prospective cohorts support an increased risk of kidney cancer in gallstone patients. Our findings provide solid evidence for the compelling need to diagnostically rule out kidney cancer before and during gallbladder removal, to prioritise kidney cancer screening in patients undergoing cholecystectomy in their 30s, and to investigate the underlying mechanisms linking gallstones and kidney cancer in future studies

Amerindian Ancestry Influences Genetic Susceptibility to Chronic Obstructive Pulmonary Disease

The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5 × 10 −4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10 −3 to 3.77 × 10 −8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent

Inbreeding, native American ancestry and child mortality:Linking human selection and paediatric medicine

The children of related parents show increased risk of early mortality. The Native American genome typically exhibits long stretches of homozygosity, and Latin Americans are highly heterogeneous regarding the individual burden of homozygosity, the proportion and the type of Native American ancestry. We analysed nationwide mortality and genome-wide genotype data from admixed Chileans to investigate the relationship between common causes of child mortality, homozygosity and Native American ancestry. Results from two-stage linear-Poisson regression revealed a strong association between the sum length of runs of homozygosity (SROH) above 1.5 Megabases (Mb) in each genome and mortality due to intracranial non-traumatic haemorrhage of foetus and newborn (5% increased risk of death per Mb in SROH, P = 1 × 10(−3)) and disorders related to short gestation and low birth weight (P = 3 × 10(−4)). The major indigenous populations in Chile are Aymara–Quechua in the north of the country and the Mapuche–Huilliche in the south. The individual proportion of Aymara–Quechua ancestry was associated with an increased risk of death due to anencephaly and similar malformations (P = 4 × 10(−5)), and the risk of death due to Edwards and Patau trisomy syndromes decreased 4% per 1% Aymara–Quechua ancestry proportion (P = 4 × 10(−4)) and 5% per 1% Mapuche–Huilliche ancestry proportion (P = 2 × 10(−3)). The present results suggest that short gestation, low birth weight and intracranial non-traumatic haemorrhage mediate the negative effect of inbreeding on human selection. Independent validation of the identified associations between common causes of child death, homozygosity and fine-scale ancestry proportions may inform paediatric medicine

Inbreeding, Native American ancestry and child mortality: linking human selection and paediatric medicine

The children of related parents show increased risk of early mortality. The Native American genome typically exhibits long stretches of homozygosity, and Latin Americans are highly heterogeneous regarding the individual burden of homozygosity, the proportion and the type of Native American ancestry. We analysed nationwide mortality and genome-wide genotype data from admixed Chileans to investigate the relationship between common causes of child mortality, homozygosity and Native American ancestry. Results from two-stage linear-Poisson regression revealed a strong association between the sum length of runs of homozygosity (SROH) above 1.5 Megabases (Mb) in each genome and mortality due to intracranial non-traumatic haemorrhage of foetus and newborn (5% increased risk of death per Mb in SROH, P = 1 × 10−3) and disorders related to short gestation and low birth weight (P = 3 × 10−4). The major indigenous populations in Chile are Aymara–Quechua in the north of the country and the Mapuche–Huilliche in the south. The individual proportion of Aymara–Quechua ancestry was associated with an increased risk of death due to anencephaly and similar malformations (P = 4 × 10−5), and the risk of death due to Edwards and Patau trisomy syndromes decreased 4% per 1% Aymara–Quechua ancestry proportion (P = 4 × 10−4) and 5% per 1% Mapuche–Huilliche ancestry proportion (P = 2 × 10−3). The present results suggest that short gestation, low birth weight and intracranial non-traumatic haemorrhage mediate the negative effect of inbreeding on human selection. Independent validation of the identified associations between common causes of child death, homozygosity and fine-scale ancestry proportions may inform paediatric medicine.Fil: Koenigstein, Fabienne. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Boekstegers, Felix. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Wilson, James F.. University of Edinburgh; Reino UnidoFil: Fuentes Guajardo, Macarena. Universidad de Tarapacá; ChileFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; ArgentinaFil: Bedoya Berrío, Gabriel. Universidad de Antioquia; ColombiaFil: Bortolini, Maria Cátira. Universidade Federal do Rio Grande do Sul; BrasilFil: Acuña Alonzo, Victor. Instituto Nacional de Antropología e Historia. Escuela Nacional de Antropología e Historia; MéxicoFil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerúFil: Ruiz-Linares, Andres. Fudan University; China. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. University College London; Reino UnidoFil: Rothhammer, Francisco. Universidad de Tarapaca. Instituto de Alta Investigación; ChileFil: Lorenzo Bermejo, Justo. Ruprecht Karls Universitat Heidelberg; Alemani

Treatment of aortic stenosis with a self-expanding transcatheter valve: the International Multi-centre ADVANCE Study

Aim Transcatheter aortic valve implantation has become an alternative to surgery in higher risk patients with symptomatic aortic stenosis. The aim of the ADVANCE study was to evaluate outcomes following implantation of a self-expanding transcatheter aortic valve system in a fully monitored, multi-centre ‘real-world' patient population in highly experienced centres. Methods and results Patients with severe aortic stenosis at a higher surgical risk in whom implantation of the CoreValve System was decided by the Heart Team were included. Endpoints were a composite of major adverse cardiovascular and cerebrovascular events (MACCE; all-cause mortality, myocardial infarction, stroke, or reintervention) and mortality at 30 days and 1 year. Endpoint-related events were independently adjudicated based on Valve Academic Research Consortium definitions. A total of 1015 patients [mean logistic EuroSCORE 19.4 ± 12.3% [median (Q1,Q3), 16.0% (10.3, 25.3%)], age 81 ± 6 years] were enrolled. Implantation of the CoreValve System led to a significant improvement in haemodynamics and an increase in the effective aortic valve orifice area. At 30 days, the MACCE rate was 8.0% (95% CI: 6.3-9.7%), all-cause mortality was 4.5% (3.2-5.8%), cardiovascular mortality was 3.4% (2.3-4.6%), and the rate of stroke was 3.0% (2.0-4.1%). The life-threatening or disabling bleeding rate was 4.0% (2.8-6.3%). The 12-month rates of MACCE, all-cause mortality, cardiovascular mortality, and stroke were 21.2% (18.4-24.1%), 17.9% (15.2-20.5%), 11.7% (9.4-14.1%), and 4.5% (2.9-6.1%), respectively. The 12-month rates of all-cause mortality were 11.1, 16.5, and 23.6% among patients with a logistic EuroSCORE ≤10%, EuroSCORE 10-20%, and EuroSCORE >20% (P< 0.05), respectively. Conclusion The ADVANCE study demonstrates the safety and effectiveness of the CoreValve System with low mortality and stroke rates in higher risk real-world patients with severe aortic stenosi

Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10−5) and Europeans (P = 9 × 10−5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10−6). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk. (Hepatology 2021;73:1783-1796).Fil: Barahona Ponce, Carol. Ruprecht Karls Universitat Heidelberg; Alemania. Universidad de Chile; ChileFil: Scherer, Dominique. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Brinster, Regina. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Boekstegers, Felix. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Marcelain, Katherine. Universidad de Chile; ChileFil: Gárate Calderón, Valentina. Ruprecht Karls Universitat Heidelberg; Alemania. Universidad de Chile; ChileFil: Müller, Bettina. Instituto Nacional del Cáncer; ChileFil: de Toro, Gonzalo. Hospital Puerto Montt; Chile. Universidad Austral de Chile; ChileFil: Retamales, Javier. Instituto Nacional del Cáncer; ChileFil: Barajas, Olga. Universidad de Chile; ChileFil: Ahumada, Monica. Universidad de Chile; ChileFil: Morales, Erik. Hospital Regional de Talca; Chile. Universidad Católica del Maule; ChileFil: Rojas, Armando. Universidad Católica del Maule; ChileFil: Sanhueza, Verónica. Hospital Padre Hurtado; ChileFil: Loader, Denisse. Hospital Padre Hurtado; ChileFil: Rivera, María Teresa. Hospital del Salvador; ChileFil: Gutiérrez, Lorena. Hospital San Juan de Dios; ChileFil: Bernal, Giuliano. Universidad Católica del Norte; ChileFil: Ortega, Alejandro. Hospital Regional; ChileFil: Montalvo, Domingo. Hospital Regional Juan Noé Crevani; ChileFil: Portiño, Sergio. Universidad de Chile; ChileFil: Bertrán, Maria Enriqueta. Ministerio de Salud; ChileFil: Gabler, Fernando. Universidad de Santiago de Chile. Hospital Clinico San Borja Arriaran; ChileFil: Spencer, Loreto. Hospital Regional Guillermo Grant Benavente; ChileFil: Olloquequi, Jordi. Universidad Autónoma de Chile; ChileFil: Fischer, Christine. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Jenab, Mazda. International Agency For Research On Cancer; AlemaniaFil: Aleksandrova, Krasimira. German Institute Of Human Nutrition; AlemaniaFil: Katzke, Verena. German Cancer Research Center; AlemaniaFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentin

Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country

Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.Fil: Boekstegers, Felix. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Scherer, Dominique. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Barahona Ponce, Carol. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Marcelain, Katherine. Universidad de Chile; ChileFil: Gárate Calderón, Valentina. Universidad de Chile; ChileFil: Waldenberger, Melanie. No especifíca;Fil: Morales, Erik. Universidad Católica de Maule; ChileFil: Rojas, Armando. Universidad Católica de Maule; ChileFil: Munoz, César. Universidad Católica de Maule; ChileFil: Retamales, Javier. Instituto Nacional del Cáncer; ChileFil: de Toro, Gonzalo. Universidad Austral de Chile; ChileFil: Barajas, Olga. Universidad de Chile; ChileFil: Rivera, María Teresa. Hospital del Salvador; ChileFil: Cortés, Analía. Hospital del Salvador; ChileFil: Loader, Denisse. Hospital Padre Hurtado; ChileFil: Saavedra, Javiera. Hospital Padre Hurtado; ChileFil: Gutiérrez, Lorena. Hospital San Juan de Dios; ChileFil: Ortega, Alejandro. Hospital Regional; ChileFil: Bertrán, Maria Enriqueta. Hospital Base de Valdivia; ChileFil: Bartolotti, Leonardo. Hospital Base de Valdivia; ChileFil: Gabler, Fernando. Hospital Clínico San Borja Arriarán; ChileFil: Campos, Mónica. Hospital Clínico San Borja Arriarán; ChileFil: Alvarado, Juan. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; ChileFil: Moisán, Fabricio. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; ChileFil: Spencer, Loreto. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; ChileFil: Nervi, Bruno. No especifíca;Fil: Carvajal Hausdorf, Daniel. Universidad del Desarrollo; ChileFil: Losada, Héctor. Universidad de La Frontera; ChileFil: Almau, Mauricio. Hospital de Rancagua; ChileFil: Fernández, Plinio. Hospital de Rancagua; ChileFil: Olloquequi, Jordi. Universidad de Barcelona; EspañaFil: Fuentes Guajardo, Macarena. Universidad de Tarapacá; ChileFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; ArgentinaFil: Bortolini, Maria Cátira. Universidade Federal do Rio Grande do Sul; BrasilFil: Acuña Alonzo, Victor. No especifíca;Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerúFil: Ruiz-Linares, Andres. Colegio Universitario de Londres; Reino UnidoFil: Rothhammer, Francisco. Universidad de Tarapacá; ChileFil: Lorenzo Bermejo, Justo. Ruprecht Karls Universitat Heidelberg; Alemani

Mendelian Randomization Analysis of the Relationship Between Native American Ancestry and Gallbladder Cancer Risk

Background A strong association between the proportion of Native American ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest Native American people in Chile. We set out to investigate the causal association between Native American Mapuche ancestry and GBC risk, and the possible mediating effects of gallstone disease and body mass index (BMI) on this association. Methods Markers of Mapuche ancestry were selected based on the informativeness for assignment measure and then used as instrumental variables in two-sample mendelian randomization (MR) analyses and complementary sensitivity analyses. Result We found evidence of a causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% for every 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.6×10-5). Mapuche ancestry was also causally linked to gallstone disease (IVW risk increase of 3.6% per 1% increase in Mapuche proportion, 95% CI 3.1% to 4.0%, p = 1.0×10-59), suggesting a mediating effect of gallstones in the relationship between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative causal effect on BMI (IVW estimate -0.006 kg/m2 per 1% increase in Mapuche proportion, 95% CI -0.009 to -0.003, p = 4.4×10-5). Conclusions The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between Mapuche ancestry and GBC risk previously noted in observational studies appears to be causal, primary and secondary prevention strategies that take into account the individual proportion of Mapuche ancestry could be particularly efficient