@article {130, title = {Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 10}, pages = {417-423}, abstract = {

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1\% in or .

RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1\% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95\% CI, 14-35]; =1.1{\texttimes}10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95\% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002871}, author = {Nomura, Akihiro and Emdin, Connor A and Won, Hong Hee and Peloso, Gina M and Natarajan, Pradeep and Ardissino, Diego and Danesh, John and Schunkert, Heribert and Correa, Adolfo and Bown, Matthew J and Samani, Nilesh J and Erdmann, Jeanette and McPherson, Ruth and Watkins, Hugh and Saleheen, Danish and Elosua, Roberto and Kawashiri, Masa-Aki and Tada, Hayato and Gupta, Namrata and Shah, Svati H and Rader, Daniel J and Gabriel, Stacey and Khera, Amit V and Kathiresan, Sekar} } @article {131, title = {A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 04}, pages = {e1008629}, abstract = {

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

}, keywords = {Alleles, Cholesterol, LDL, Coronary Artery Disease, Datasets as Topic, Fatty Liver, Female, Genetic Predisposition to Disease, Homozygote, Humans, Liver, Liver Cirrhosis, Liver Cirrhosis, Alcoholic, Loss of Function Mutation, Male, Middle Aged, Mitochondrial Proteins, Mutation, Missense, Oxidoreductases}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008629}, author = {Emdin, Connor A and Haas, Mary E and Khera, Amit V and Aragam, Krishna and Chaffin, Mark and Klarin, Derek and Hindy, George and Jiang, Lan and Wei, Wei-Qi and Feng, Qiping and Karjalainen, Juha and Havulinna, Aki and Kiiskinen, Tuomo and Bick, Alexander 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 Saleheen, Danish and Chang, Kyong-Mi and Vujkovic, Marijana and Voight, Ben and Damrauer, Scott and Lynch, Julie and Kaplan, David and Serper, Marina and Tsao, Philip and Mercader, Josep and Hanis, Craig and Daly, Mark and Denny, Joshua and Gabriel, Stacey and Kathiresan, Sekar} } @article {114, title = {A structural variation reference for medical and population genetics.}, journal = {Nature}, volume = {581}, year = {2020}, month = {2020 05}, pages = {444-451}, abstract = {

Structural variants (SVs) rearrange large segments of DNA and can have profound consequences in evolution and human disease. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral in the interpretation of single-nucleotide variants (SNVs). However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54\% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29\% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9\% of samples, and estimate that 0.13\% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings. This SV resource is freely distributed via the gnomAD browser and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

}, keywords = {Continental Population Groups, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Reference Standards, Selection, Genetic, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2287-8}, author = {Collins, Ryan L and Brand, Harrison and Karczewski, Konrad J and Zhao, Xuefang and Alf{\"o}ldi, Jessica and Francioli, Laurent C and Khera, Amit V and Lowther, Chelsea and Gauthier, Laura D and Wang, Harold and Watts, Nicholas A and Solomonson, Matthew and O{\textquoteright}Donnell-Luria, Anne and Baumann, Alexander and Munshi, Ruchi and Walker, Mark and Whelan, Christopher W and Huang, Yongqing and Brookings, Ted and Sharpe, Ted and Stone, Matthew R and Valkanas, Elise and Fu, Jack and Tiao, Grace and Laricchia, Kristen M and Ruano-Rubio, Valentin and Stevens, Christine and Gupta, Namrata and Cusick, Caroline and Margolin, Lauren and Taylor, Kent D and Lin, Henry J and Rich, Stephen S and Post, Wendy S and Chen, Yii-Der Ida and Rotter, Jerome I and Nusbaum, Chad and Philippakis, Anthony and Lander, Eric and Gabriel, Stacey and Neale, Benjamin M and Kathiresan, Sekar and Daly, Mark J and Banks, Eric and MacArthur, Daniel G and Talkowski, Michael E} } @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} } @article {36, title = {Characterization and remediation of sample index swaps by non-redundant dual indexing on massively parallel sequencing platforms.}, journal = {BMC Genomics}, volume = {19}, year = {2018}, month = {2018 May 08}, pages = {332}, abstract = {

BACKGROUND: Here we present an in-depth characterization of the mechanism of sequencer-induced sample contamination due to the phenomenon of index swapping that impacts Illumina sequencers employing patterned flow cells with Exclusion Amplification (ExAmp) chemistry (HiSeqX, HiSeq4000, and NovaSeq). We also present a remediation method that minimizes the impact of such swaps.

RESULTS: Leveraging data collected over a two-year period, we demonstrate the widespread prevalence of index swapping in patterned flow cell data. We calculate mean swap rates across multiple sample preparation methods and sequencer models, demonstrating that different library methods can have vastly different swapping rates and that even non-ExAmp chemistry instruments display trace levels of index swapping. We provide methods for eliminating sample data cross contamination by utilizing non-redundant dual indexing for complete filtering of index swapped reads, and share the sequences for 96 non-combinatorial dual indexes we have validated across various library preparation methods and sequencer models. Finally, using computational methods we provide a greater insight into the mechanism of index swapping.

CONCLUSIONS: Index swapping in pooled libraries is a prevalent phenomenon that we observe at a rate of 0.2 to 6\% in all sequencing runs on HiSeqX, HiSeq 4000/3000, and NovaSeq. Utilizing non-redundant dual indexing allows for the removal (flagging/filtering) of these swapped reads and eliminates swapping induced sample contamination, which is critical for sensitive applications such as RNA-seq, single cell, blood biopsy using circulating tumor DNA, or clinical sequencing.

}, keywords = {DNA, Gene Library, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, Sequence Analysis, DNA}, issn = {1471-2164}, doi = {10.1186/s12864-018-4703-0}, author = {Costello, Maura and Fleharty, Mark and Abreu, Justin and Farjoun, Yossi and Ferriera, Steven and Holmes, Laurie and Granger, Brian and Green, Lisa and Howd, Tom and Mason, Tamara and Vicente, Gina and Dasilva, Michael and Brodeur, Wendy and DeSmet, Timothy and Dodge, Sheila and Lennon, Niall J and Gabriel, Stacey} } @article {12, title = {ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.}, journal = {J Am Coll Cardiol}, volume = {69}, year = {2017}, month = {2017 Apr 25}, pages = {2054-2063}, abstract = {

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3~major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3~wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were~defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in~<25\% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17\% reduction in circulating triglycerides and a 12\% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34\% reduction in odds of CAD (odds ratio: 0.66; 95\% confidence interval: 0.44 to 0.98; p~= 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95\% confidence interval: 0.55 to 0.77; p~< 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

}, keywords = {Adult, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins, Angiopoietins, Animals, Atherosclerosis, Case-Control Studies, Coronary Artery Disease, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Missense, Myocardial Infarction, Risk Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2017.02.030}, author = {Stitziel, Nathan O and Khera, Amit V and Wang, Xiao and Bierhals, Andrew J and Vourakis, A Christina and Sperry, Alexandra E and Natarajan, Pradeep and Klarin, Derek and Emdin, Connor A and Zekavat, Seyedeh M and Nomura, Akihiro and Erdmann, Jeanette and Schunkert, Heribert and Samani, Nilesh J and Kraus, William E and Shah, Svati H and Yu, Bing and Boerwinkle, Eric and Rader, Daniel J and Gupta, Namrata and Frossard, Philippe M and Rasheed, Asif and Danesh, John and Lander, Eric S and Gabriel, Stacey and Saleheen, Danish and Musunuru, Kiran and Kathiresan, Sekar} }