@article {155, title = {Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {431-445}, abstract = {

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

}, keywords = {African Americans, Aged, Aged, 80 and over, Calbindin 2, Colitis, Ulcerative, Crohn Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Receptors, Prostaglandin E, EP4 Subtype, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.001}, author = {Somineni, Hari K and Nagpal, Sini and Venkateswaran, Suresh and Cutler, David J and Okou, David T and Haritunians, Talin and Simpson, Claire L and Begum, Ferdouse and Datta, Lisa W and Quiros, Antonio J and Seminerio, Jenifer and Mengesha, Emebet and Alexander, Jonathan S and Baldassano, Robert N and Dudley-Brown, Sharon and Cross, Raymond K and Dassopoulos, Themistocles and Denson, Lee A and Dhere, Tanvi A and Iskandar, Heba and Dryden, Gerald W and Hou, Jason K and Hussain, Sunny Z and Hyams, Jeffrey S and Isaacs, Kim L and Kader, Howard and Kappelman, Michael D and Katz, Jeffry and Kellermayer, Richard and Kuemmerle, John F and Lazarev, Mark and Li, Ellen and Mannon, Peter and Moulton, Dedrick E and Newberry, Rodney D and Patel, Ashish S and Pekow, Joel and Saeed, Shehzad A and Valentine, John F and Wang, Ming-Hsi and McCauley, Jacob L and Abreu, Maria T and Jester, Traci and Molle-Rios, Zarela and Palle, Sirish and Scherl, Ellen J and Kwon, John and Rioux, John D and Duerr, Richard H and Silverberg, Mark S and Zwick, Michael E and Stevens, Christine and Daly, Mark J and Cho, Judy H and Gibson, Greg and McGovern, Dermot P B and Brant, Steven R and Kugathasan, Subra} } @article {121, title = {What Is Familial Hypercholesterolemia, and Why Does It Matter?}, journal = {Circulation}, volume = {141}, year = {2020}, month = {2020 06 02}, pages = {1760-1763}, keywords = {Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Humans, Hyperlipoproteinemia Type II, Prevalence}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.120.046961}, author = {Khera, Amit V and Hegele, Robert A} } @article {107, title = {Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late.}, journal = {Clin Genet}, volume = {98}, year = {2020}, month = {2020 11}, pages = {477-485}, abstract = {

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1\%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3\%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50\% of them.

}, issn = {1399-0004}, doi = {10.1111/cge.13823}, author = {Minardi, Raffaella and Licchetta, Laura and Baroni, Maria Chiara and Pippucci, Tommaso and Stipa, Carlotta and Mostacci, Barbara and Severi, Giulia and Toni, Francesco and Bergonzini, Luca and Carelli, Valerio and Seri, Marco and Tinuper, Paolo and Bisulli, Francesca} } @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 {42, title = {Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.}, journal = {Am J Respir Crit Care Med}, volume = {197}, year = {2018}, month = {2018 Jun 15}, pages = {1552-1564}, abstract = {

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 {\texttimes} 10) and suggestive (P < 7.06 {\texttimes} 10) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

}, issn = {1535-4970}, doi = {10.1164/rccm.201712-2529OC}, author = {Mak, Angel C Y and White, Marquitta J and Eckalbar, Walter L and Szpiech, Zachary A and Oh, Sam S and Pino-Yanes, Maria and Hu, Donglei and Goddard, Pag{\'e} and Huntsman, Scott and Galanter, Joshua and Wu, Ann Chen and Himes, Blanca E and Germer, Soren and Vogel, Julia M and Bunting, Karen L and Eng, Celeste and Salazar, Sandra and Keys, Kevin L and Liberto, Jennifer and Nuckton, Thomas J and Nguyen, Thomas A and Torgerson, Dara G and Kwok, Pui-Yan and Levin, Albert M and Celed{\'o}n, Juan C and Forno, Erick and Hakonarson, Hakon and Sleiman, Patrick M and Dahlin, Amber and Tantisira, Kelan G and Weiss, Scott T and Serebrisky, Denise and Brigino-Buenaventura, Emerita and Farber, Harold J and Meade, Kelley and Lenoir, Michael A and Avila, Pedro C and Sen, Saunak and Thyne, Shannon M and Rodriguez-Cintron, William and Winkler, Cheryl A and Moreno-Estrada, Andr{\'e}s and Sandoval, Karla and Rodriguez-Santana, Jose R and Kumar, Rajesh and Williams, L Keoki and Ahituv, Nadav and Ziv, Elad and Seibold, Max A and Darnell, Robert B and Zaitlen, Noah and Hernandez, Ryan D and Burchard, Esteban G} }