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Quantitative CMR population imaging on 20,000 subjects of the UK Biobank imaging study: LV/RV quantification pipeline and its evaluation
Type: article, Author: Rahman Attara and Marco Pereañez and Ali Gooya and Xènia Albàd and Le Zhang and Milton Hozd and Vilaa Aaron and M.Leef and NayAung and Elena Lukaschuke and Mihir M.Sanghvi and Kenneth Fung and Jose Miguel Paiv and Stefan K.Piechnike and Stefan Neubauer and Steffen E.Petersen and Alejandro F.Frangi, Date: 2019-08-01
Reflections on Randomized Trials and Observational Studies
Type: article, Author: Sir Rory Collins and John D. Rutherford, Date: 2019-07-08
Air pollution, lung function and COPD: results from the population-based UK Biobank study
Type: article, Author: Dany Doiron and Kees de Hoogh and Nicole Probst-Hensch and Isabel Fortier and Yutong Cai and Sara De Matteis and Anna L. Hansell, Date: 2019-07-08
Last updated Jan 15, 2019
2019 |
Derek Klarin; Julie Lynch; Krishna Aragam; Mark Chaffin; Themistocles L. Assimes; Jie Huang; Kyung Min Lee; Qing Shao; Jennifer E. Huffman; Pradeep Natarajan; Shipra Arya; Aeron Small; Yan V. Sun; Marijana Vujkovic; Matthew S. Freiberg; Lu Wang; Jinbo Chen; Danish Saleheen; Jennifer S. Lee; Donald R. Miller; Peter Reaven; Patrick R. Alba; Olga V. Patterson; Scott L. DuVall; William E. Boden; Joshua A. Beckman; J. Michael Gaziano; John Concato; Daniel J. Rader; Kelly Cho; Kyong-Mi Chang; Peter W. F. Wilson; Christopher J. O’Donnell; Sekar Kathiresan; VA Million Veteran Program; Philip S. Tsao; Scott M. Damrauer Genome-wide association of peripheral artery disease in the Million Veteran Program Journal Article In: Nature Medicine, 2019. Abstract | Links | BibTeX | Tags: 7089, artery disease, genetics @article{Klarin2019, title = {Genome-wide association of peripheral artery disease in the Million Veteran Program}, author = {Derek Klarin and Julie Lynch and Krishna Aragam and Mark Chaffin and Themistocles L. Assimes and Jie Huang and Kyung Min Lee and Qing Shao and Jennifer E. Huffman and Pradeep Natarajan and Shipra Arya and Aeron Small and Yan V. Sun and Marijana Vujkovic and Matthew S. Freiberg and Lu Wang and Jinbo Chen and Danish Saleheen and Jennifer S. Lee and Donald R. Miller and Peter Reaven and Patrick R. Alba and Olga V. Patterson and Scott L. DuVall and William E. Boden and Joshua A. Beckman and J. Michael Gaziano and John Concato and Daniel J. Rader and Kelly Cho and Kyong-Mi Chang and Peter W. F. Wilson and Christopher J. O’Donnell and Sekar Kathiresan and VA Million Veteran Program and Philip S. Tsao and Scott M. Damrauer }, url = {https://www.nature.com/articles/s41591-019-0492-5}, year = {2019}, date = {2019-07-08}, journal = {Nature Medicine}, abstract = {Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.}, keywords = {7089, artery disease, genetics}, pubstate = {published}, tppubtype = {article} } Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights. |
G Hindy; KE Åkesson; O Melander; KG Aragam; ME Haas; PM Nilsson; UT Kadam; M Orho-Melander In: Arthritis and Rheumatology, 2019. Abstract | Links | BibTeX | Tags: 7089, cardiometabolic, genetics, ostearthritis @article{Hindy2019, title = {Cardiometabolic polygenic risk scores and osteoarthritis outcomes: a Mendelian randomization study from the Malmӧ Diet and Cancer Study and the UK Biobank}, author = {G Hindy and KE Åkesson and O Melander and KG Aragam and ME Haas and PM Nilsson and UT Kadam and M Orho-Melander }, url = {https://www.ncbi.nlm.nih.gov/pubmed/30615301}, year = {2019}, date = {2019-01-07}, journal = {Arthritis and Rheumatology}, abstract = {OBJECTIVE: To investigate the causal role of cardiometabolic risk factors in osteoarthritis (OA) using associated genetic variants. METHODS: We studied 27691 adults from the Malmö Diet and Cancer Study (MDCS) and replicated novel findings among 376435 adults from the UK Biobank. Trait-specific polygenic risk scores for LDL- and HDL-cholesterol (LDLC, HDLC), triglycerides (TG), BMI, fasting plasma glucose (FPG) and systolic blood pressure (SBP) were used to test the associations of genetically predicted elevations in each trait with incident OA-diagnosis (n=3559), OA-joint replacement (n=2780), or both (total-OA, n=4226) in Mendelian randomization (MR) analyses in MDCS, and with self-reported and/or hospital diagnosed OA (n=65213) in the UK Biobank. Multivariable MR, MR-Egger and weighted-median MR were used to adjust for potential pleiotropic biases. RESULTS: In MDCS, genetically predicted higher LDLC was associated with lower risk of OA-diagnosis (OR: 0.83; 95% CI: 0.73-0.95 per 1-SD) and total-OA (0.87; 0.78-0.98) which was supported by multivariable MR for OA-diagnosis (0.84; 0.75-0.95) and total-OA (0.87; 0.78-0.97), and by conventional two-sample MR for OA-diagnosis (0.86; 0.75-0.98). MR-Egger indicated no pleiotropic bias. Genetically predicted higher BMI was associated with increased risk for OA-diagnosis (1.65; 1.14-2.41), while MR-Egger indicated pleiotropic bias and larger association with OA-diagnosis (3.25; 1.26-8.39), OA-joint replacement (3.81; 1.39-10.4) and total-OA (3.41; 1.43-8.15). No associations were observed between genetically predicted HDLC, TG, FPG or SBP and OA outcomes. The LDLC associations were replicated in the UK Biobank (0.95; 0.93-0.98). CONCLUSION: Our MR study provides evidence for causal role of lower LDLC and higher BMI in OA. This article is protected by copyright. All rights reserved.}, keywords = {7089, cardiometabolic, genetics, ostearthritis}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To investigate the causal role of cardiometabolic risk factors in osteoarthritis (OA) using associated genetic variants. METHODS: We studied 27691 adults from the Malmö Diet and Cancer Study (MDCS) and replicated novel findings among 376435 adults from the UK Biobank. Trait-specific polygenic risk scores for LDL- and HDL-cholesterol (LDLC, HDLC), triglycerides (TG), BMI, fasting plasma glucose (FPG) and systolic blood pressure (SBP) were used to test the associations of genetically predicted elevations in each trait with incident OA-diagnosis (n=3559), OA-joint replacement (n=2780), or both (total-OA, n=4226) in Mendelian randomization (MR) analyses in MDCS, and with self-reported and/or hospital diagnosed OA (n=65213) in the UK Biobank. Multivariable MR, MR-Egger and weighted-median MR were used to adjust for potential pleiotropic biases. RESULTS: In MDCS, genetically predicted higher LDLC was associated with lower risk of OA-diagnosis (OR: 0.83; 95% CI: 0.73-0.95 per 1-SD) and total-OA (0.87; 0.78-0.98) which was supported by multivariable MR for OA-diagnosis (0.84; 0.75-0.95) and total-OA (0.87; 0.78-0.97), and by conventional two-sample MR for OA-diagnosis (0.86; 0.75-0.98). MR-Egger indicated no pleiotropic bias. Genetically predicted higher BMI was associated with increased risk for OA-diagnosis (1.65; 1.14-2.41), while MR-Egger indicated pleiotropic bias and larger association with OA-diagnosis (3.25; 1.26-8.39), OA-joint replacement (3.81; 1.39-10.4) and total-OA (3.41; 1.43-8.15). No associations were observed between genetically predicted HDLC, TG, FPG or SBP and OA outcomes. The LDLC associations were replicated in the UK Biobank (0.95; 0.93-0.98). CONCLUSION: Our MR study provides evidence for causal role of lower LDLC and higher BMI in OA. This article is protected by copyright. All rights reserved. |
Connor A Emdin; Amit V Khera; Krishna Aragam; Mary Haas; Mark Chaffin; Derek Klarin; Pradeep Natarajan; Alexander Bick; Seyedeh M Zekavat; Akihiro Nomura; Diego Ardissino; James G Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J Bown; Nilesh J Samani; Usman Baber; Jeanette Erdmann; Namrata Gupta; John Danesh; Danish Saleheen; Stacey Gabriel; Sekar; Kathiresan In: Diabetes, 2019. Abstract | Links | BibTeX | Tags: 7089, diabetes, genetics @article{Emdin2019, title = {DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes}, author = {Connor A Emdin and Amit V Khera and Krishna Aragam and Mary Haas and Mark Chaffin and Derek Klarin and Pradeep Natarajan and Alexander Bick and Seyedeh M Zekavat and Akihiro Nomura and Diego Ardissino and James G Wilson and Heribert Schunkert and Ruth McPherson and Hugh Watkins and Roberto Elosua and Matthew J Bown and Nilesh J Samani and Usman Baber and Jeanette Erdmann and Namrata Gupta and John Danesh and Danish Saleheen and Stacey Gabriel and Sekar and Kathiresan}, url = {http://diabetes.diabetesjournals.org/content/68/1/226.long}, year = {2019}, date = {2019-01-01}, journal = {Diabetes}, abstract = {A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (−0.09 SD}, keywords = {7089, diabetes, genetics}, pubstate = {published}, tppubtype = {article} } A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (−0.09 SD |
2018 |
Krishna G Aragam; Mark Chaffin; Rebecca T Levinson; Gregory McDermott; Seung-Hoan Choi; Benjamin M Shoemaker; Mary E Haasan; Lu-Chen Weng; Mark E Lindsay; Gustav J Smith; Christopher Newton-Cheh; Dan M Roden; Barry London; Quinn S Wells; Patrick T Ellinor; Sekar Kathiresan; Steven A Lubitz Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery Journal Article In: Circulation, 2018. Abstract | Links | BibTeX | Tags: 17488, 7089, genetics, heart failure @article{Aragam2018, title = {Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery}, author = {Krishna G Aragam and Mark Chaffin and Rebecca T Levinson and Gregory McDermott and Seung-Hoan Choi and Benjamin M Shoemaker and Mary E Haasan and Lu-Chen Weng and Mark E Lindsay and Gustav J Smith and Christopher Newton-Cheh and Dan M Roden and Barry London and Quinn S Wells and Patrick T Ellinor and Sekar Kathiresan and Steven A Lubitz}, url = {https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.118.035774}, year = {2018}, date = {2018-11-11}, journal = {Circulation}, abstract = {Background: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30201). Results: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10-6), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-offunction variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10-5). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.}, keywords = {17488, 7089, genetics, heart failure}, pubstate = {published}, tppubtype = {article} } Background: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30201). Results: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10-6), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-offunction variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10-5). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction. |
Mary E Haas; Krishna G Aragam; Connor A Emdin; Alexander G Bick; International Consortium Blood for Pressure; Gibran Hemani; George Davey Smith; Sekar Kathiresan Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure Journal Article In: American Journal of Human Genetics, 2018. Abstract | Links | BibTeX | Tags: 7089, blood pressure, featured, genetics @article{Haas2018, title = {Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure}, author = {Mary E Haas and Krishna G Aragam and Connor A Emdin and Alexander G Bick and International Consortium Blood for Pressure and Gibran Hemani and George Davey Smith and Sekar Kathiresan}, url = {https://www.cell.com/ajhg/fulltext/S0002-9297(18)30270-2}, year = {2018}, date = {2018-09-13}, journal = {American Journal of Human Genetics}, abstract = {Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases. Genetically elevated albuminuria was strongly associated with increased risk of hypertension (1.38 OR; 95% CI, 1.27–1.50 per 1 SD predicted increase in albuminuria}, keywords = {7089, blood pressure, featured, genetics}, pubstate = {published}, tppubtype = {article} } Excretion of albumin in urine, or albuminuria, is associated with the development of multiple cardiovascular and metabolic diseases. However, whether pathways leading to albuminuria are causal for cardiometabolic diseases is unclear. We addressed this question using a Mendelian randomization framework in the UK Biobank, a large population-based cohort. We first performed a genome-wide association study for albuminuria in 382,500 individuals and identified 32 new albuminuria loci. We constructed albuminuria genetic risk scores and tested for association with cardiometabolic diseases. Genetically elevated albuminuria was strongly associated with increased risk of hypertension (1.38 OR; 95% CI, 1.27–1.50 per 1 SD predicted increase in albuminuria |
Amit V Khera; Mark Chaffin; Krishna G Aragam; Mary E Haas; Carolina Roselli; Seung Hoan Choi; Pradeep Natarajan; Eric S Lander; Steven A Lubitz; Patrick T Ellinor; Sekar Kathiresan Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations Journal Article In: Nature Genetics, 2018. Abstract | Links | BibTeX | Tags: 7089, common disease, featured, genetics @article{Khera2018, title = {Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations}, author = {Amit V Khera and Mark Chaffin and Krishna G Aragam and Mary E Haas and Carolina Roselli and Seung Hoan Choi and Pradeep Natarajan and Eric S Lander and Steven A Lubitz and Patrick T Ellinor and Sekar Kathiresan}, url = {https://www.nature.com/articles/s41588-018-0183-z}, year = {2018}, date = {2018-08-13}, journal = {Nature Genetics}, abstract = {A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2,3,4,5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.}, keywords = {7089, common disease, featured, genetics}, pubstate = {published}, tppubtype = {article} } A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2,3,4,5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues. |
Connor A Emdin; Amit V Khera; Mark Chaffin; Derek Klarin; Pradeep Natarajan; Krishna Aragam; Mary Haas; Alexander Bick; Seyedeh M Zekavat; Akihiro Nomura; Diego Ardissino; James G Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J Bown; Nilesh J Samani; Usman Baber; Jeanette Erdmann; Namrata Gupta; John Danesh; Daniel Chasman; Paul Ridker; Joshua Denny; Lisa Bastarache; Judith H Lichtman; Gail D’Onofrio; Jennifer Mattera; John A Spertus; Wayne H -H Sheu; Kent D Taylor; Bruce M Psaty; Stephen S Rich; Wendy Post; Jerome I Rotter; Yii-Der Ida Chen; Harlan Krumholz; Danish Saleheen; Stacey Gabriel; Sekar Kathiresan - Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease Journal Article In: Nature Communications, 2018. Abstract | Links | BibTeX | Tags: 7089, disease, genetics, protection @article{Emdin2018, title = {Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease}, author = {Connor A Emdin and Amit V Khera and Mark Chaffin and Derek Klarin and Pradeep Natarajan and Krishna Aragam and Mary Haas and Alexander Bick and Seyedeh M Zekavat and Akihiro Nomura and Diego Ardissino and James G Wilson and Heribert Schunkert and Ruth McPherson and Hugh Watkins and Roberto Elosua and Matthew J Bown and Nilesh J Samani and Usman Baber and Jeanette Erdmann and Namrata Gupta and John Danesh and Daniel Chasman and Paul Ridker and Joshua Denny and Lisa Bastarache and Judith H Lichtman and Gail D’Onofrio and Jennifer Mattera and John A Spertus and Wayne H -H Sheu and Kent D Taylor and Bruce M Psaty and Stephen S Rich and Wendy Post and Jerome I Rotter and Yii-Der Ida Chen and Harlan Krumholz and Danish Saleheen and Stacey Gabriel and Sekar Kathiresan -}, url = {https://www.nature.com/articles/s41467-018-03911-8}, year = {2018}, date = {2018-04-24}, journal = {Nature Communications}, abstract = {Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.}, keywords = {7089, disease, genetics, protection}, pubstate = {published}, tppubtype = {article} } Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease. |
2017 |
Dajiang J Liu; Gina M Peloso; Sekar Kathiresan Exome-wide association study of plasma lipids in >300,000 individuals Journal Article In: Nature Genetics, 2017. Abstract | Links | BibTeX | Tags: 7089, genetics @article{Liu2017, title = {Exome-wide association study of plasma lipids in >300,000 individuals}, author = {Dajiang J Liu and Gina M Peloso and Sekar Kathiresan}, url = {https://www.nature.com/articles/ng.3977}, year = {2017}, date = {2017-10-30}, journal = {Nature Genetics}, abstract = {We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.}, keywords = {7089, genetics}, pubstate = {published}, tppubtype = {article} } We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. |
Connor A Emdin; Amit V Khera; Derek Klarin; Pradeep Natarajan; Seyedeh M Zekavat; Akihiro Nomura; Mary E Haas; Krishna Aragam; Diego Ardissino; James G Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J Bown; Nilesh J Samani; Usman Baber; Jeanette Erdmann; Padhraig Gormley; Aarno Palotie; Nathan Stitziel; Namrata Gupta; John N Danesh; Danish Saleheen; Stacey B Gabriel; Sekar Kathiresan Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling Journal Article In: circulation, 2017. Abstract | Links | BibTeX | Tags: 7089, featured, genetics, phenotypes @article{Emdin2017b, title = {Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling}, author = {Connor A Emdin and Amit V Khera and Derek Klarin and Pradeep Natarajan and Seyedeh M Zekavat and Akihiro Nomura and Mary E Haas and Krishna Aragam and Diego Ardissino and James G Wilson and Heribert Schunkert and Ruth McPherson and Hugh Watkins and Roberto Elosua and Matthew J Bown and Nilesh J Samani and Usman Baber and Jeanette Erdmann and Padhraig Gormley and Aarno Palotie and Nathan Stitziel and Namrata Gupta and John N Danesh and Danish Saleheen and Stacey B Gabriel and Sekar Kathiresan}, url = {http://circ.ahajournals.org/content/early/2017/10/04/CIRCULATIONAHA.117.028021?utm_content=buffer79393&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer}, year = {2017}, date = {2017-10-05}, journal = {circulation}, abstract = {Background—Nitric oxide signaling plays a key role in regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacologic stimulation of the nitric oxide pathway as a therapeutic strategy. Methods—We analyzed the association of common and rare genetic variants in two genes that mediate nitric oxide signaling [Nitric Oxide Synthase 3 (NOS3) and Guanylate Cyclase 1, Soluble, Alpha 3 (GUCY1A3)] with a range of human phenotypes. We selected two common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335,464 participants in the UK Biobank and summary association results from seven large-scale genome wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27,815). Results—A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease [OR 0.37 95% CI 0.31, 0.45; p=5.5*10-26], peripheral arterial disease (OR 0.42 CI 0.26, 0.68; p=0.0005) and stroke (OR 0.53 CI 0.37, 0.76; p=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (CI 12, 34 mm Hg; p=5.6*10-5) and a three-fold higher risk of coronary heart disease (OR 3.03 CI 1.29, 7.12}, keywords = {7089, featured, genetics, phenotypes}, pubstate = {published}, tppubtype = {article} } Background—Nitric oxide signaling plays a key role in regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacologic stimulation of the nitric oxide pathway as a therapeutic strategy. Methods—We analyzed the association of common and rare genetic variants in two genes that mediate nitric oxide signaling [Nitric Oxide Synthase 3 (NOS3) and Guanylate Cyclase 1, Soluble, Alpha 3 (GUCY1A3)] with a range of human phenotypes. We selected two common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335,464 participants in the UK Biobank and summary association results from seven large-scale genome wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27,815). Results—A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease [OR 0.37 95% CI 0.31, 0.45; p=5.5*10-26], peripheral arterial disease (OR 0.42 CI 0.26, 0.68; p=0.0005) and stroke (OR 0.53 CI 0.37, 0.76; p=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (CI 12, 34 mm Hg; p=5.6*10-5) and a three-fold higher risk of coronary heart disease (OR 3.03 CI 1.29, 7.12 |
Derek Klarin; Qiuyu Martin Zhu; Connor A Emdin; Mark Chaffin; Steven Horner; Brian J McMillan; Alison Leed; Michael E Weale; Chris C A Spencer; Ayellet Segrè V François Aguet; and Kristin G Ardlie; Amit V Khera; Virendar K Kaushik; Pradeep Natarajan; CARDIoGRAMplusC4D Consortium; Sekar Kathiresan Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease Journal Article In: Nature Genetics, 2017. Abstract | Links | BibTeX | Tags: 7089, featured, genetics, heart disease, insulin @article{Klarin2017b, title = {Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease}, author = {Derek Klarin and Qiuyu Martin Zhu and Connor A Emdin and Mark Chaffin and Steven Horner and Brian J McMillan and Alison Leed and Michael E Weale and Chris C A Spencer and Ayellet Segrè V François Aguet and and Kristin G Ardlie and Amit V Khera and Virendar K Kaushik and Pradeep Natarajan and CARDIoGRAMplusC4D Consortium and Sekar Kathiresan}, url = {http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3914.html?foxtrotcallback=true}, year = {2017}, date = {2017-07-17}, journal = {Nature Genetics}, abstract = {UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry1. We performed a genome-wide association study in UK Biobank testing ~9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes.}, keywords = {7089, featured, genetics, heart disease, insulin}, pubstate = {published}, tppubtype = {article} } UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry1. We performed a genome-wide association study in UK Biobank testing ~9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes. |
Natarajan CARDIOGRAM Exome JC Florez Kathiresan AV Khera AV P S consortium CA Emdin D Klarin Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease Journal Article In: Diabetes, 2017. Abstract | Links | BibTeX | Tags: 7089, genetics, heart disease, type 2 diabetes @article{Emdin2017b, title = {Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease}, author = {Natarajan CARDIOGRAM Exome JC Florez Kathiresan AV Khera AV P S consortium CA Emdin D Klarin}, url = {https://www.ncbi.nlm.nih.gov/pubmed/28411266}, year = {2017}, date = {2017-04-14}, journal = {Diabetes}, abstract = {Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacologic therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120 286 participants in the UK Biobank and summary association results from four large-scale genome wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (OR 0.93 95%CI 0.91, 0.95; p=1.2×10-11). The variant was associated with increased body mass index (0.062 CI 0.037, 0.086 kg/m2; p=8.1×10-7) but lower waist-to-hip ratio adjusted for body mass index, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98 CI 0.96, 0.99; p=5.9×10-4). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.}, keywords = {7089, genetics, heart disease, type 2 diabetes}, pubstate = {published}, tppubtype = {article} } Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacologic therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120 286 participants in the UK Biobank and summary association results from four large-scale genome wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (OR 0.93 95%CI 0.91, 0.95; p=1.2×10-11). The variant was associated with increased body mass index (0.062 CI 0.037, 0.086 kg/m2; p=8.1×10-7) but lower waist-to-hip ratio adjusted for body mass index, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98 CI 0.96, 0.99; p=5.9×10-4). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease. |
Natarajan MF Conrad INVENT Consortium Kathiresan P S D Klarin CA Emdin Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor Journal Article In: Circulation. Cardiovascular genetics, 2017. Abstract | Links | BibTeX | Tags: 7089, genetics, obesity, Venous Thromboembolism @article{Klarin2017b, title = {Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor}, author = {Natarajan MF Conrad INVENT Consortium Kathiresan P S D Klarin CA Emdin}, url = {https://www.ncbi.nlm.nih.gov/pubmed/28373160}, year = {2017}, date = {2017-04-10}, journal = {Circulation. Cardiovascular genetics}, abstract = {BACKGROUND: UK Biobank is the world's largest repository for phenotypic and genotypic information for individuals of European ancestry. Here, we leverage UK Biobank to understand the inherited basis for venous thromboembolism (VTE), a leading cause of cardiovascular mortality. METHODS AND RESULTS: We identified 3290 VTE cases and 116 868 controls through billing code-based phenotyping. We performed a genome-wide association study for VTE with ≈9 000 000 imputed single-nucleotide polymorphisms. We performed a phenome-wide association study for a genetic risk score of 10 VTE-associated variants. To assess whether obesity is a causal factor for VTE, we performed Mendelian randomization analysis using a genetic risk score instrument composed of 68 body mass index-associated variants. The genome-wide association study for VTE replicated previous findings at the F5, F2, ABO, F11, and FGG loci. We identified 1 new locus-ZFPM2 rs4602861-at genome-wide significance (odds ratio, 1.11; 95% confidence interval, 1.07-1.15; P=4.9×10-10) and a new independent variant at the F2 locus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06-1.13; P=7.60×10-9). In a phenome-wide association study, a 10 single-nucleotide polymorphism VTE genetic risk score was associated with coronary artery disease (odds ratio, 1.08; 95% confidence interval, 1.05-1.10 per unit increase in VTE odds; P=1.08×10-9). In a Mendelian randomization analysis, genetically elevated body mass index (a 1 SD increase) was associated with 57% higher risk of VTE (odds ratio, 1.57; 95% confidence interval, 1.08-1.97; P=0.003). CONCLUSIONS: For common diseases such as VTE, biobanks provide potential to perform genetic discovery, explore the phenotypic consequences for disease-associated variants, and test causal inference.}, keywords = {7089, genetics, obesity, Venous Thromboembolism}, pubstate = {published}, tppubtype = {article} } BACKGROUND: UK Biobank is the world's largest repository for phenotypic and genotypic information for individuals of European ancestry. Here, we leverage UK Biobank to understand the inherited basis for venous thromboembolism (VTE), a leading cause of cardiovascular mortality. METHODS AND RESULTS: We identified 3290 VTE cases and 116 868 controls through billing code-based phenotyping. We performed a genome-wide association study for VTE with ≈9 000 000 imputed single-nucleotide polymorphisms. We performed a phenome-wide association study for a genetic risk score of 10 VTE-associated variants. To assess whether obesity is a causal factor for VTE, we performed Mendelian randomization analysis using a genetic risk score instrument composed of 68 body mass index-associated variants. The genome-wide association study for VTE replicated previous findings at the F5, F2, ABO, F11, and FGG loci. We identified 1 new locus-ZFPM2 rs4602861-at genome-wide significance (odds ratio, 1.11; 95% confidence interval, 1.07-1.15; P=4.9×10-10) and a new independent variant at the F2 locus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06-1.13; P=7.60×10-9). In a phenome-wide association study, a 10 single-nucleotide polymorphism VTE genetic risk score was associated with coronary artery disease (odds ratio, 1.08; 95% confidence interval, 1.05-1.10 per unit increase in VTE odds; P=1.08×10-9). In a Mendelian randomization analysis, genetically elevated body mass index (a 1 SD increase) was associated with 57% higher risk of VTE (odds ratio, 1.57; 95% confidence interval, 1.08-1.97; P=0.003). CONCLUSIONS: For common diseases such as VTE, biobanks provide potential to perform genetic discovery, explore the phenotypic consequences for disease-associated variants, and test causal inference. |
Connor A Emdin; Amit V Khera; Pradeep Natarajan; Derek Klarin; Seyedeh M Zekavat; Allan J; Hsiao; Sekar; Kathiresan Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease Journal Article In: JAMA, 2017. Abstract | Links | BibTeX | Tags: 7089, genetics @article{Emdin2017c, title = {Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease}, author = {Connor A Emdin and Amit V Khera and Pradeep Natarajan and Derek Klarin and Seyedeh M Zekavat and Allan J and Hsiao and Sekar and Kathiresan}, url = {http://www.kathiresanlab.org/wp-content/uploads/2017/03/Emdin-JAMA-2-17.pdf}, year = {2017}, date = {2017-02-14}, journal = {JAMA}, abstract = {IMPORTANCE In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain. OBJECTIVE To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes. DESIGN, SETTING, AND PARTICIPANTS A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank. EXPOSURES Genetic predisposition to increased WHR adjusted for BMI. MAIN OUTCOMES AND MEASURES Type 2 diabetes and CHD. RESULTS Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1–mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440). CONCLUSIONS AND RELEVANCE A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes}, keywords = {7089, genetics}, pubstate = {published}, tppubtype = {article} } IMPORTANCE In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain. OBJECTIVE To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes. DESIGN, SETTING, AND PARTICIPANTS A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank. EXPOSURES Genetic predisposition to increased WHR adjusted for BMI. MAIN OUTCOMES AND MEASURES Type 2 diabetes and CHD. RESULTS Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1–mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440). CONCLUSIONS AND RELEVANCE A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes |
2016 |
Amit Natarajan Pradeep Klarin Derek Won Hong-Hee Peloso Gina Stitziel Nathan Nomura Akihiro Zekavat Seyedeh Bick Alexander Gupta Namrata Asselta Rosanna Duga Stefano Merlini Piera Angelica Correa Adolfo Kessler Thorsten Wilson James Bown Matthew Hall Alistair Braund Peter Samani Nilesh Schunkert Heribert Marrugat Jaume Elosua Roberto McPherson Ruth Farrall Martin Watkins Hugh Willer Cristen Abecasis Gonçalo Felix Janine Vasan Ramachandran Lander Eric Rader Daniel Danesh John Ardissino Diego Gabriel Stacey Saleheen Danish Kathiresan Sekar V M O M G G J S S J R F S J Emdin Connor A. Khera Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels Journal Article In: Journal of the American College of Cardiology, 2016. Abstract | Links | BibTeX | Tags: 7089, Human lipoprotein(a) @article{EmdinCA2016, title = {Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels}, author = {Amit Natarajan Pradeep Klarin Derek Won Hong-Hee Peloso Gina Stitziel Nathan Nomura Akihiro Zekavat Seyedeh Bick Alexander Gupta Namrata Asselta Rosanna Duga Stefano Merlini Piera Angelica Correa Adolfo Kessler Thorsten Wilson James Bown Matthew Hall Alistair Braund Peter Samani Nilesh Schunkert Heribert Marrugat Jaume Elosua Roberto McPherson Ruth Farrall Martin Watkins Hugh Willer Cristen Abecasis Gonçalo Felix Janine Vasan Ramachandran Lander Eric Rader Daniel Danesh John Ardissino Diego Gabriel Stacey Saleheen Danish Kathiresan Sekar V M O M G G J S S J R F S J Emdin Connor A. Khera}, url = {http://www.onlinejacc.org/content/accj/68/25/2761.full.pdf}, year = {2016}, date = {2016-12-27}, journal = {Journal of the American College of Cardiology}, abstract = {Background Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation.Objectives The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD.Methods We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.Results One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.Conclusions Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.%U}, keywords = {7089, Human lipoprotein(a)}, pubstate = {published}, tppubtype = {article} } Background Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation.Objectives The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD.Methods We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.Results One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.Conclusions Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.%U |
