@article {50, title = {Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.}, journal = {Circulation}, volume = {139}, year = {2019}, month = {2019 Mar 26}, pages = {1593-1602}, abstract = {

BACKGROUND: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.

METHODS: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age <=55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5\% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.

RESULTS: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66\% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7\%) and was associated with a 3.8-fold (95\% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3\%) carried a high polygenic score, associated with a 3.7-fold (95\% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).

CONCLUSIONS: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.035658}, author = {Khera, Amit V and Chaffin, Mark and Zekavat, Seyedeh M and Collins, Ryan L and Roselli, Carolina and Natarajan, Pradeep and Lichtman, Judith H and D{\textquoteright}Onofrio, Gail and Mattera, Jennifer and Dreyer, Rachel and Spertus, John A and Taylor, Kent D and Psaty, Bruce M and Rich, Stephen S and Post, Wendy and Gupta, Namrata and Gabriel, Stacey and Lander, Eric and Ida Chen, Yii-Der and Talkowski, Michael E and Rotter, Jerome I and Krumholz, Harlan M and Kathiresan, Sekar} } @article {38, title = {Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Apr 24}, pages = {1613}, 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 = {Databases, Genetic, Diabetes Mellitus, Type 2, Disease, Gene Frequency, Genetic Testing, Genetic Variation, Humans, Obesity, Phenotype, Proteins, Respiratory Hypersensitivity, United Kingdom}, issn = {2041-1723}, doi = {10.1038/s41467-018-03911-8}, author = {Emdin, Connor A and Khera, Amit V and Chaffin, Mark and Klarin, Derek and Natarajan, Pradeep and Aragam, Krishna and Haas, Mary and Bick, Alexander and Zekavat, Seyedeh M and Nomura, Akihiro and Ardissino, Diego and Wilson, James G and Schunkert, Heribert and McPherson, Ruth and Watkins, Hugh and Elosua, Roberto and Bown, Matthew J and Samani, Nilesh J and Baber, Usman and Erdmann, Jeanette and Gupta, Namrata and Danesh, John and Chasman, Daniel and Ridker, Paul and Denny, Joshua and Bastarache, Lisa and Lichtman, Judith H and D{\textquoteright}Onofrio, Gail and Mattera, Jennifer and Spertus, John A and Sheu, Wayne H-H and Taylor, Kent D and Psaty, Bruce M and Rich, Stephen S and Post, Wendy and Rotter, Jerome I and Chen, Yii-Der Ida and Krumholz, Harlan and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} }