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1. PMS2CL interference leading to erroneous identification of a pathogenic PMS2 variant in Black patients

Author: Jacqueline Cappadocia, Lisa B. Aiello, Michael J. Kelley, Bryson W. Katona, Kara N. Maxwell, Anurag Verma, Ph.D., Shefali S. Verma, Ph.D., Yuki Bradford, M.S., Ashlei Brock, Stephanie DerOhannessian, Scott Dudek, M.S., Joseph Dunn, Theodore Drivas, M.D., Ph.D., Ned Haubein, Khadijah Hu-Sain, Renae Judy, Ashley Kloter, Yi-An Ko, Meghan Livingstone, Linda Morrel, Colleen Morse, M.S., Afiya Poindexter, Marjorie Risman, M.S., Teo Tran, Fred Vadivieso, JoEllen Weaver, Daniel J. Rader, M.D., Marylyn D. Ritchie, Ph.D., Michael D. Feldman, M.D., Ph.D., Christina Beechert, Caitlin Forsythe, M.S., Erin D. Fuller, Zhenhua Gu, M.S., Michael Lattari, Alexander Lopez, M.S., John D. Overton, Ph.D., Maria Sotiropoulos Padilla, M.S., Manasi Pradhan, M.S., Kia Manoochehri, B.S., Thomas D. Schleicher, M.S., Louis Widom, Sarah E. Wolf, M.S., Ricardo H. Ulloa, B.S., Amelia Averitt, Ph.D., Nilanjana Banerjee, Ph.D., Michael Cantor, M.D., Dadong Li, Ph.D., Sameer Malhotra, M.D., Deepika Sharma, MHI, Jeffrey Staples, Ph.D., Xiaodong Bai, Ph.D., Suganthi Balasubramanian, Ph.D., Suying Bao, Ph.D., Boris Boutkov, Ph.D., Siying Chen, Ph.D., Gisu Eom, B.S., Lukas Habegger, Ph.D., Alicia Hawes, B.S., Shareef Khalid, Olga Krasheninina, M.S., Rouel Lanche, B.S., Adam J. Mansfield, B.A., Evan K. Maxwell, Ph.D., George Mitra, B.A., Mona Nafde, M.S., Sean O’Keeffe, Ph.D., Max Orelus, B.B.A., Razvan Panea, Ph.D., Tommy Polanco, B.A., Ayesha Rasool, M.S., Jeffrey G. Reid, Ph.D., William Salerno, Ph.D., Jeffrey C. Staples, Ph.D., Kathie Sun, Ph.D., Goncalo Abecasis, D.Phil., Joshua Backman, Ph.D., Amy Damask, Ph.D., Lee Dobbyn, Ph.D., Manuel Allen Revez Ferreira, Ph.D., Arkopravo Ghosh, M.S., Christopher Gillies, Ph.D., Lauren Gurski, B.S., Eric Jorgenson, Ph.D., Hyun Min Kang, Ph.D., Michael Kessler, Ph.D., Jack Kosmicki, Ph.D., Alexander Li, Ph.D., Nan Lin, Ph.D., Daren Liu, M.S., Adam Locke, Ph.D., Jonathan Marchini, Ph.D., Anthony Marcketta, M.S., Joelle Mbatchou, Ph.D., Arden Moscati, Ph.D., Charles Paulding, Ph.D., Carlo Sidore, Ph.D., Eli Stahl, Ph.D., Kyoko Watanabe, Ph.D., Bin Ye, Ph.D., Blair Zhang, Ph.D., Andrey Ziyatdinov, Ph.D., Ariane Ayer, B.S., Aysegul Guvenek, Ph.D., George Hindy, Ph.D., Giovanni Coppola, M.D., Jan Freudenberg, M.D., Jonas Bovijn, M.D., Katherine Siminovitch, M.D., Kavita Praveen, Ph.D., Luca A. Lotta, M.D., Manav Kapoor, Ph.D., Mary Haas, Ph.D., Moeen Riaz, Ph.D., Niek Verweij, Ph.D., Olukayode Sosina, Ph.D., Parsa Akbari, Ph.D., Priyanka Nakka, Ph.D., Sahar Gelfman, Ph.D., Sujit Gokhale, B.E., Tanima De, Ph.D., Veera Rajagopal, Ph.D., Alan Shuldiner, M.D., Gannie Tzoneva, Ph.D., Juan Rodriguez-Flores, Ph.D., Esteban Chen, M.S., Marcus B. Jones, Ph.D., Michelle G. LeBlanc, Ph.D., Jason Mighty, Ph.D., Lyndon J. Mitnaul, Ph.D., Nirupama Nishtala, Ph.D., Nadia Rana, Ph.D., Jaimee Hernandez, Goncalo Abecasis, PhD, Aris Baras, M.D., Andrew Deubler, Aris Economides, Ph.D., and Luca A. Lotta, M.D., Ph.D.
Subjects: PMS2, germline genetic testing, Lynch syndrome, PMS2CL, pseudogene interference, Genetics, QH426-470, Medicine
Abstract: This study investigates the frequency of a clinically reported variant in PMS2, NM_000535.7:c.2523G>A p.(W841∗), from next-generation sequencing studies in 2 racially diverse cohorts. We identified clinical reports of the PMS2 c.2523G>A p.(W841∗) variant in the National Precision Oncology Program’s somatic testing database (n = 25,168). We determined frequency of the variant in germline exome sequencing from the Penn Medicine BioBank (n = 44,256) and in gnomAD. The PMS2 c.2523G>A p.(W841∗) was identified as a homozygous variant on tumor testing in an adult patient of self-identified Black race/ethnicity with no evidence of constitutional mismatch repair deficiency. The variant was clinically reported on 35 total tumor and liquid biopsy tests (0.1%), and all individuals with the variant were of self-identified Black race/ethnicity (0.6% of n = 5787). In individuals of African genetic ancestry (AFR), the variant's germline frequency was reported to be 0.2% and 1.3% in the Penn Medicine BioBank (PMBB) and gnomAD, respectively. The variant cannot be found in any individuals of European genetic ancestry (EUR) from either of the databases. The variant is found in a region of PMS2 with 100% homology to the PMS2CL pseudogene. PMS2 c.2523G>A p.(W841∗), when identified, is typically an African-ancestry-specific PMS2CL pseudogene variant, which should be recognized to prevent misdiagnosis of Lynch syndrome in Blacks.
Published: 2024
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2. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Author: Parsa Akbari, Olukayode A. Sosina, Jonas Bovijn, Karl Landheer, Jonas B. Nielsen, Minhee Kim, Senem Aykul, Tanima De, Mary E. Haas, George Hindy, Nan Lin, Ian R. Dinsmore, Jonathan Z. Luo, Stefanie Hectors, Benjamin Geraghty, Mary Germino, Lampros Panagis, Prodromos Parasoglou, Johnathon R. Walls, Gabor Halasz, Gurinder S. Atwal, Regeneron Genetics Center, DiscovEHR Collaboration, Marcus Jones, Michelle G. LeBlanc, Christopher D. Still, David J. Carey, Alice Giontella, Marju Orho-Melander, Jaime Berumen, Pablo Kuri-Morales, Jesus Alegre-Díaz, Jason M. Torres, Jonathan R. Emberson, Rory Collins, Daniel J. Rader, Brian Zambrowicz, Andrew J. Murphy, Suganthi Balasubramanian, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Michael Cantor, Goncalo R. Abecasis, Manuel A. R. Ferreira, Mark W. Sleeman, Viktoria Gusarova, Judith Altarejos, Charles Harris, Aris N. Economides, Vincent Idone, Katia Karalis, Giusy Della Gatta, Tooraj Mirshahi, George D. Yancopoulos, Olle Melander, Jonathan Marchini, Roberto Tapia-Conyer, Adam E. Locke, Aris Baras, Niek Verweij, and Luca A. Lotta
Subjects: Science
Abstract: Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.
Published: 2022
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3. Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Author: Julie E. Horowitz, Neil Warner, Jeffrey Staples, Eileen Crowley, Nehal Gosalia, Ryan Murchie, Cristopher Van Hout, Karoline Fiedler, Gabriel Welch, Alejandra Klauer King, Jeffrey G. Reid, John D. Overton, Aris Baras, Alan R. Shuldiner, Anne Griffiths, Omri Gottesman, Aleixo M. Muise, and Claudia Gonzaga-Jauregui
Subjects: Medicine, Science
Abstract: Abstract Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.
Published: 2021
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4. Causal Effect of Adiposity Measures on Blood Pressure Traits in 2 Urban Swedish Cohorts: A Mendelian Randomization Study

Author: Alice Giontella, Luca A. Lotta, John D. Overton, Aris Baras, Pietro Minuz, Olle Melander, Dipender Gill, and Cristiano Fava
Subjects: adiposity, blood pressure, genetics, Mendelian randomization, polymorphisms, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Different adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this. Methods and Results In this study, we used 4 different genetic risk scores (GRS; GRS‐BMI565, GRS‐WHR324, GRS‐VAT208, GRS‐BF81) including hundreds of single nucleotide polymorphisms associated with body mass index, waist‐to‐hip ratio, visceral adipose tissue, and body fat, respectively. These were applied as instrumental variables in Mendelian randomization analyses. Two Swedish urban‐based cohort studies, the Malmö Diet and Cancer, and the Malmö Preventive 795Projects were used to obtain genetic association estimates with blood pressure (BP). In both the Malmö Preventive Projects and Malmö Diet and Cancer studies, except for that for body fat, all of the genetic risk scores were significantly associated with systolic BP and diastolic BP, but with different magnitudes. In particular, in both cohorts, each standard deviation increase in the genetic risk score made up by the 324 single nucleotide polymorphisms associated with waist‐to‐hip ratio was associated with doubling of the likelihood of hypertension prevalence at baseline. However, only the genetic risk score made up by the 565 SNPs associated with body mass index was significantly associated with hypertension incidence during 23.6±4.3 years of follow‐up in the Malmö Preventive Project. Conclusions We support a causal link between genetically mediated adiposity, especially waist‐to‐hip ratio and body mass index, and BP traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity affects BP/hypertension and consequently may indicate that tailored interventions are needed to reduce cardiovascular risk.
Published: 2021
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5. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Author: Na Zhu, Carrie L. Welch, Jiayao Wang, Philip M. Allen, Claudia Gonzaga-Jauregui, Lijiang Ma, Alejandra K. King, Usha Krishnan, Erika B. Rosenzweig, D. Dunbar Ivy, Eric D. Austin, Rizwan Hamid, Michael W. Pauciulo, Katie A. Lutz, William C. Nichols, Jeffrey G. Reid, John D. Overton, Aris Baras, Frederick E. Dewey, Yufeng Shen, and Wendy K. Chung
Subjects: Pulmonary hypertension, Congenital heart disease, Exome sequencing, Genetic association study, Medicine, Genetics, QH426-470
Abstract: Abstract Background Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD. Methods To identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene. Results We identified SOX17 as a novel candidate risk gene (p = 5.5e−7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases. Conclusions These data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.
Published: 2018
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6. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author: Viktoria Gusarova, Colm O’Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, Michael F. Murray, Anubha Mahajan, Jonas B. Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F. Gudbjartsson, Marketa Sjögren, Connor A. Emdin, Robert A. Scott, Wen-Jane Lee, Aeron Small, Lydia C. Kwee, Om Prakash Dwivedi, Rashmi B. Prasad, Shannon Bruse, Alexander E. Lopez, John Penn, Anthony Marcketta, Joseph B. Leader, Christopher D. Still, H. Lester Kirchner, Uyenlinh L. Mirshahi, Amr H. Wardeh, Cassandra M. Hartle, Lukas Habegger, Samantha N. Fetterolf, Teresa Tusie-Luna, Andrew P. Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I. Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M. Brummett, Amit V. Khera, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A. Lotta, Cristen J. Willer, Oddgeir L. Holmen, Marylyn D. Ritchie, David H. Ledbetter, Andrew J. Murphy, Ingrid B. Borecki, Jeffrey G. Reid, John D. Overton, Ola Hansson, Leif Groop, Svati H. Shah, William E. Kraus, Daniel J. Rader, Yii-Der I. Chen, Kristian Hveem, Nicholas J. Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Goncalo R. Abecasis, David Altshuler, Jose C. Florez, Michael Boehnke, Mark I. McCarthy, George D. Yancopoulos, David J. Carey, Alan R. Shuldiner, Aris Baras, Frederick E. Dewey, and Jesper Gromada
Subjects: Science
Abstract: Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4 −/− mice on a high-fat diet show improved insulin sensitivity.
Published: 2018
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7. KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

Author: Emily Breidbart, MD, Lauren Golden, MD, Claudia Gonzaga-Jauregui, PhD, Liyong Deng, MD, Patricia Lanzano, BA, Charles LeDuc, PhD, JianCheng Guo, MD, PhD, John D. Overton, PhD, Jeffery Reid, PhD, Alan Shuldiner, MD, and Wendy K. Chung, MD, PhD
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ABSTRACT: Objective: To present a case of adult-onset familial diabetes mellitus in which a genetic etiology typical for neonatal diabetes was identified.Methods: We conducted whole-exome and Sanger sequencing, assessed clinical presentation and family history, and performed a literature review.Results: A 40-year-old, thin woman presented with a 10-year history of mildly elevated fasting glucose and A1C levels. Her mother had diabetes mellitus since her 40s and is on insulin, and her daughter presented with diabetes mellitus at age 21. The patient and her daughter underwent whole-exome sequencing and were found to have a mutation in the KCNJ11 gene, c.G685A, p.E229K. This mutation is known to be associated with neonatal presentation of diabetes mellitus, which neither of these family members had a history of. Given her known mutation and postprandial hyperglycemia, a trial of low-dose sulfonylurea was initiated in the daughter but failed due to hypoglycemia. She was found to have a CYP2C9 genotype associated with poor oral drug clearance.Conclusion:KCNJ11 mutation should be screened for in patients and families meeting criteria for maturity-onset diabetes of the young, even without evidence of neonatal onset in the family. Furthermore, even though sulfonylurea therapy is successful in the majority of patients with KCNJ11 mutations, there may be a role for other interacting environmental or genetic modifiers, such as CYP2C9 geno-type, that affect sulfonylurea metabolism. Those patients who have delayed onset of disease and milder courses may be less ideal candidates for this treatment.Abbreviations: BMI = body mass index;KATP = ATP-sensitive potassium channel;MODY = maturity-onset diabetes of the young;NDM = neonatal diabetes mellitus
Published: 2018
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8. Measuring Absolute RNA Copy Numbers at High Temporal Resolution Reveals Transcriptome Kinetics in Development

Author: Nick D.L. Owens, Ira L. Blitz, Maura A. Lane, Ilya Patrushev, John D. Overton, Michael J. Gilchrist, Ken W.Y. Cho, and Mustafa K. Khokha
Subjects: Biology (General), QH301-705.5
Abstract: Transcript regulation is essential for cell function, and misregulation can lead to disease. Despite technologies to survey the transcriptome, we lack a comprehensive understanding of transcript kinetics, which limits quantitative biology. This is an acute challenge in embryonic development, where rapid changes in gene expression dictate cell fate decisions. By ultra-high-frequency sampling of Xenopus embryos and absolute normalization of sequence reads, we present smooth gene expression trajectories in absolute transcript numbers. During a developmental period approximating the first 8 weeks of human gestation, transcript kinetics vary by eight orders of magnitude. Ordering genes by expression dynamics, we find that “temporal synexpression” predicts common gene function. Remarkably, a single parameter, the characteristic timescale, can classify transcript kinetics globally and distinguish genes regulating development from those involved in cellular metabolism. Overall, our analysis provides unprecedented insight into the reorganization of maternal and embryonic transcripts and redefines our ability to perform quantitative biology.
Published: 2016
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9. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

Author: Shan Dong, Michael F. Walker, Nicholas J. Carriero, Michael DiCola, A. Jeremy Willsey, Adam Y. Ye, Zainulabedin Waqar, Luis E. Gonzalez, John D. Overton, Stephanie Frahm, John F. Keaney, III, Nicole A. Teran, Jeanselle Dea, Jeffrey D. Mandell, Vanessa Hus Bal, Catherine A. Sullivan, Nicholas M. DiLullo, Rehab O. Khalil, Jake Gockley, Zafer Yuksel, Sinem M. Sertel, A. Gulhan Ercan-Sencicek, Abha R. Gupta, Shrikant M. Mane, Michael Sheldon, Andrew I. Brooks, Kathryn Roeder, Bernie Devlin, Matthew W. State, Liping Wei, and Stephan J. Sanders
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0–2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10−9), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. : Insertions and deletions (indels) have proven especially difficult to detect in exome sequencing data. Dong et al. now identify indels in exome data for 787 autism spectrum disorder (ASD) families. They demonstrate association between de novo indels that alter the reading frame and ASD. Furthermore, by observing clustering of indels in unrelated probands, they uncover two additional ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
Published: 2014
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10. Genetic Susceptibility to Mood Disorders and Risk of Stroke: A Polygenic Risk Score and Mendelian Randomization Study

Author: Jiangming Sun, Yan Borné, Andreas Edsfeldt, Yunpeng Wang, Mengyu Pan, Olle Melander, Gunnar Engström, Isabel Gonçalves, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Young Hahn, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Ashish Yadav, Marcus B. Jones, and Lyndon J. Mitnaul
Subjects: Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract: Background: Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and causal roles of mood disorders in stroke. Methods: We tested if genetic susceptibilities for mood disorders were associated with all strokes, ischemic strokes in the Malmö Diet and Cancer cohort (24 631 individuals with a median follow-up of 21.3 (interquartile range: 16.6–23.2) years. We further examined the causal effects for mood disorders on all strokes and ischemic strokes using summary statistics from large genome-wide association studies of mood disorders (up to 609 424 individuals, Psychiatric Genomics Consortium), all strokes and ischemic strokes (up to 446 696 individuals, MEGASTROKE Consortium). Results: Among 24 366 stroke-free participants at baseline, 2632 individuals developed strokes, 2172 of them ischemic, during follow-up. After properly adjusting for well-known risk factors, participants in the highest quintile of polygenic risk scores for mood disorders had 1.45× (95% CI, 1.21–1.74) higher risk of strokes and 1.44× (95% CI, 1.18–1.76) higher risk of ischemic strokes compared with the lowest quintile in women. Mendelian randomization analyses suggested that mood disorders had a causal effect on strokes (odds ratio, 1.07 [95% CI, 1.03–1.11]) and ischemic strokes (odds ratio, 1.09 [95% CI, 1.04–1.13]). Conclusions: Our results suggest a causal role of mood disorders in the risk of stroke. High-risk women could be identified early in life using polygenic risk scores to ultimately prevent mood disorders and strokes.
Published: 2023
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11. Identifying Genetic Associations with Variability in Metabolic Health and Blood Count Laboratory Values: Diving into the Quantitative Traits by Leveraging Longitudinal Data from an EHR.

Author: Shefali S. Verma, Anastasia Lucas, Daniel R. Lavage, Joseph B. Leader, Raghu Metpally, Sarathbabu Krishnamurthy, Frederick E. Dewey, Ingrid B. Borecki, Alexander E. Lopez, John D. Overton, John Penn, Jeffrey G. Reid, Sarah A. Pendergrass, Gerda Breitwieser, and Marylyn D. Ritchie
Published: 2017

12. Integrating Clinical Laboratory Measures and ICD-9 Code Diagnoses in Phenome-Wide Association Studies.

Author: Anurag Verma, Joseph B. Leader, Shefali S. Verma, Alex T. Frase, John R. Wallace, Scott M. Dudek, Daniel R. Lavage, Cristopher V. Van Hout, Frederick E. Dewey, John Penn, Alexander E. Lopez, John D. Overton, David J. Carey, David H. Ledbetter, H. Lester Kirchner, Marylyn D. Ritchie, and Sarah A. Pendergrass
Published: 2016

13. Germline Mutations in CIDEB and Protection against Liver Disease

Author: Niek Verweij, Mary E. Haas, Jonas B. Nielsen, Olukayode A. Sosina, Minhee Kim, Parsa Akbari, Tanima De, George Hindy, Jonas Bovijn, Trikaldarshi Persaud, Lawrence Miloscio, Mary Germino, Lampros Panagis, Kyoko Watanabe, Joelle Mbatchou, Marcus Jones, Michelle LeBlanc, Suganthi Balasubramanian, Craig Lammert, Sofia Enhörning, Olle Melander, David J. Carey, Christopher D. Still, Tooraj Mirshahi, Daniel J. Rader, Prodromos Parasoglou, Johnathon R. Walls, John D. Overton, Jeffrey G. Reid, Aris Economides, Michael N. Cantor, Brian Zambrowicz, Andrew J. Murphy, Goncalo R. Abecasis, Manuel A.R. Ferreira, Eriks Smagris, Viktoria Gusarova, Mark Sleeman, George D. Yancopoulos, Jonathan Marchini, Hyun M. Kang, Katia Karalis, Alan R. Shuldiner, Giusy Della Gatta, Adam E. Locke, Aris Baras, and Luca A. Lotta
Subjects: General Medicine
Published: 2022
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14. Thrombotic risk determined by rare and common SERPINA1 variants in a population‐based cohort study

Author: Eric Manderstedt, Christer Halldén, Christina Lind‐Halldén, Johan Elf, Peter J. Svensson, Gunnar Engström, Olle Melander, Aris Baras, Luca A. Lotta, Bengt Zöller, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Kia Manoochehri, Maria Sotiropoulos Padilla, Manasi Pradhan, Thomas D. Schleicher, Ricardo H. Ulloa, Louis Widom, Sarah E. Wolf, Xiaodong Bai, Suganthi Balasubramanian, Andrew Blumenfeld, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mrunali Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Jason Mighty, and Lyndon J. Mitnaul
Subjects: Aged, 80 and over, Cohort Studies, Male, Genotype, Case-Control Studies, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency, Humans, Female, Thrombosis, Venous Thromboembolism, Hematology, Aged
Abstract: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study.This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study.The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Individuals were followed from baseline until the first event of VTE, death, or 2018.Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF)0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0-10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE.The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population-based Swedish study.
Published: 2022
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15. Clinical Implications of the Amyloidogenic V122I Transthyretin Variant in the General Population

Author: Susan A Matulevicius, Aris Baras, Ambarish Pandey, James A. de Lemos, Colby Ayers, Julia Kozlitina, Sonia Garg, Krishnasree Rao, Justin L. Grodin, Jeffrey S. Reid, Mark H. Drazner, Jarett D. Berry, and John D. Overton
Subjects: endocrine system, medicine.medical_specialty, medicine.drug_class, Population, Gastroenterology, Article, Cardiac magnetic resonance imaging, Interquartile range, Internal medicine, medicine, Natriuretic peptide, Humans, Prealbumin, education, Heart Failure, education.field_of_study, medicine.diagnostic_test, biology, business.industry, Amyloidosis, nutritional and metabolic diseases, medicine.disease, Black or African American, Transthyretin, Cardiac amyloidosis, Heart failure, Mutation, biology.protein, Cardiology and Cardiovascular Medicine, business
Abstract: The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population.TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P.05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P.001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers.V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.
Published: 2022
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16. Inference of Causal Relationships Between Genetic Risk Factors for Cardiometabolic Phenotypes and Female‐Specific Health Conditions

Author: Brenda Xiao, Digna R. Velez Edwards, Anastasia Lucas, Theodore Drivas, Kathryn Gray, Brendan Keating, Chunhua Weng, Gail P. Jarvik, Hakon Hakonarson, Leah Kottyan, Noemie Elhadad, Wei‐Qi Wei, Yuan Luo, Dokyoon Kim, Marylyn Ritchie, Shefali Setia Verma, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Katia Karalis, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiropoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D. Schleicher, Louis Widom, Sarah E. Wolf, Ricardo H. Ulloa, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Deepika Sharma, Jeffrey Staples, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, George Mitra, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C. Staples, Kathie Sun, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Alexander Li, Nan Lin, Daren Liu, Adam Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Ariane Ayer, Aysegul Guvenek, George Hindy, Jan Freudenberg, Jonas Bovijn, Kavita Praveen, Manav Kapoor, Mary Haas, Moeen Riaz, Niek Verweij, Olukayode Sosina, Parsa Akbari, Priyanka Nakka, Sahar Gelfman, Sujit Gokhale, Tanima De, Veera Rajagopal, Gannie Tzoneva, Juan Rodriguez‐Flores, Shek Man Chim, Valerio Donato, Daniel Fernandez, Giusy Della Gatta, Alessandro Di Gioia, Kristen Howell, Lori Khrimian, Minhee Kim, Hector Martinez, Lawrence Miloscio, Sheilyn Nunez, Elias Pavlopoulos, Trikaldarshi Persaud, Esteban Chen, Marcus B. Jones, Michelle G. LeBlanc, Jason Mighty, Lyndon J. Mitnaul, Nirupama Nishtala, and Nadia Rana
Subjects: Cardiology and Cardiovascular Medicine
Abstract: Background Cardiometabolic diseases are highly comorbid, but their relationship with female‐specific or overwhelmingly female‐predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross‐trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to women. Methods and Results Using electronic health record data from 71 008 ancestrally diverse women, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index, coronary artery disease, type 2 diabetes, and hypertension) by performing 4 analyses: (1) cross‐trait genetic correlation analyses to compare genetic architecture, (2) polygenic risk score–based association tests to characterize shared genetic effects on disease risk, (3) Mendelian randomization for significant associations to assess cross‐trait causal relationships, and (4) chronology analyses to visualize the timeline of events unique to groups of women with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age. We observed 27 significant associations between cardiometabolic polygenic scores and obstetrical/gynecological conditions (body mass index and endometrial cancer, body mass index and polycystic ovarian syndrome, type 2 diabetes and gestational diabetes, type 2 diabetes and polycystic ovarian syndrome). Mendelian randomization analysis provided additional evidence of independent causal effects. We also identified an inverse association between coronary artery disease and breast cancer. High cardiometabolic polygenic scores were associated with early development of polycystic ovarian syndrome and gestational hypertension. Conclusions We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female‐specific health conditions.
Published: 2023
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17. CLAMMS: a scalable algorithm for calling common and rare copy number variants from exome sequencing data.

Author: Jonathan S. Packer, Evan K. Maxwell, Colm O'Dushlaine, Alexander E. Lopez, Frederick E. Dewey, Rostislav Chernomorsky, Aris Baras, John D. Overton, Lukas Habegger, and Jeffrey G. Reid
Published: 2016
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18. Genome‐wide association analysis of serum alanine and aspartate aminotransferase, and the modifying effects of BMI in 388k European individuals

Author: Chuan Gao, Anthony Marcketta, Joshua D. Backman, Colm O'Dushlaine, Jeffrey Staples, Manuel Allen Revez Ferreira, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Tooraj Mirshahi, null Regeneron Genetics Center, null Geisinger Regeneron Discovehr Collaboration, Aris Baras, Gonçalo Abecasis, Alan R. Shuldiner, Cristopher V. Van Hout, and Shane McCarthy
Subjects: ALT, Epidemiology, interaction, Physiology, Genome-wide association study, digestive system, Body Mass Index, 03 medical and health sciences, Liver disease, Genome-Wide Association Analysis, medicine, Humans, GWAS, Aspartate Aminotransferases, AST, Research Articles, Genetics (clinical), 030304 developmental biology, Genetic association, Alanine, 0303 health sciences, business.industry, 030305 genetics & heredity, Alanine Transaminase, medicine.disease, digestive system diseases, Genetic architecture, Minor allele frequency, liver disease, business, Body mass index, Genome-Wide Association Study, Research Article
Abstract: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are biomarkers for liver health. Here we report the largest genome‐wide association analysis to date of serum ALT and AST levels in over 388k people of European ancestry from UK biobank and DiscovEHR. Eleven million imputed markers with a minor allele frequency (MAF) ≥ 0.5% were analyzed. Overall, 300 ALT and 336 AST independent genome‐wide significant associations were identified. Among them, 81 ALT and 61 AST associations are reported for the first time. Genome‐wide interaction study identified 9 ALT and 12 AST independent associations significantly modified by body mass index (BMI), including several previously reported potential liver disease therapeutic targets, for example, PNPLA3, HSD17B13, and MARC1. While further work is necessary to understand the effect of ALT and AST‐associated variants on liver disease, the weighted burden of significant BMI‐modified signals is significantly associated with liver disease outcomes. In summary, this study identifies genetic associations which offer an important step forward in understanding the genetic architecture of serum ALT and AST levels. Significant interactions between BMI and genetic loci not only highlight the important role of adiposity in liver damage but also shed light on the genetic etiology of liver disease in obese individuals.
Published: 2021
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19. Germline Mutations in

Author: Niek, Verweij, Mary E, Haas, Jonas B, Nielsen, Olukayode A, Sosina, Minhee, Kim, Parsa, Akbari, Tanima, De, George, Hindy, Jonas, Bovijn, Trikaldarshi, Persaud, Lawrence, Miloscio, Mary, Germino, Lampros, Panagis, Kyoko, Watanabe, Joelle, Mbatchou, Marcus, Jones, Michelle, LeBlanc, Suganthi, Balasubramanian, Craig, Lammert, Sofia, Enhörning, Olle, Melander, David J, Carey, Christopher D, Still, Tooraj, Mirshahi, Daniel J, Rader, Prodromos, Parasoglou, Johnathon R, Walls, John D, Overton, Jeffrey G, Reid, Aris, Economides, Michael N, Cantor, Brian, Zambrowicz, Andrew J, Murphy, Goncalo R, Abecasis, Manuel A R, Ferreira, Eriks, Smagris, Viktoria, Gusarova, Mark, Sleeman, George D, Yancopoulos, Jonathan, Marchini, Hyun M, Kang, Katia, Karalis, Alan R, Shuldiner, Giusy, Della Gatta, Adam E, Locke, Aris, Baras, and Luca A, Lotta
Subjects: Liver, Liver Diseases, Exome Sequencing, Humans, Genetic Predisposition to Disease, Apoptosis Regulatory Proteins, Germ-Line Mutation, Transaminases
Abstract: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants inRare germline mutations in
Published: 2022

20. Heterozygosity for a Pathogenic Variant in SLC12A3 That Causes Autosomal Recessive Gitelman Syndrome Is Associated with Lower Serum Potassium

Author: Elizabeth A. Streeten, John D. Overton, Jeffrey S. Reid, Braxton D. Mitchell, Feng Jin, Mao Fu, James A. Perry, Xuesi Wan, Kathleen A. Ryan, Yanbing Li, Aris Baras, Haichen Zhang, Zhe Han, Alan R. Shuldiner, and Cristopher V. Van Hout
Subjects: medicine.medical_specialty, Potassium, chemistry.chemical_element, Heterozygote advantage, General Medicine, Gitelman syndrome, Biology, Heritability, medicine.disease, Loss of heterozygosity, Endocrinology, chemistry, Nephrology, Internal medicine, medicine, Old Order Amish, Exome sequencing, Subclinical infection
Abstract: Background Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known. Methods A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake. Results A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G SLC12A3) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers. Conclusions This study provides evidence that heterozygosity for a pathogenic variant in SLC12A3 causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into SLC12A3 biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.
Published: 2021
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21. Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Author: David J. Carey, Cristen J. Willer, Anthony Marcketta, Claudia Schurmann, Leland Barnard, John Penn, Suganthi Balasubramanian, Daren Liu, Joseph B. Leader, Gonçalo R. Abecasis, Marcus B. Jones, John C. Whittaker, Ashutosh K. Pandey, Ida Surakka, David H. Ledbetter, Evan Maxwell, John D. Overton, Andrew Blumenfeld, Michael N. Cantor, Robert A. Scott, Wendy K. Chung, Alexander H. Li, Alexander Lopez, Joshua D. Backman, Matthew R. Nelson, Jeffrey Staples, Giovanni Coppola, Jonathan Marchini, Xiaodong Bai, Kavita Praveen, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Aris N. Economides, Shareef Khalid, William J Salerno, Bin Ye, Cristopher V. Van Hout, Kristian Hveem, Jeffrey G. Reid, Colm O'Dushlaine, Joshua D. Hoffman, Laura M. Yerges-Armstrong, Nilanjana Banerjee, Sean O'Keeffe, Ioanna Tachmazidou, Lon R. Cardon, Alicia Hawes, Aris Baras, Ashish Yadav, George D. Yancopoulos, and Lukas Habegger
Subjects: Male, 0301 basic medicine, Genes, BRCA2, Genes, BRCA1, Hasso-Plattner-Institut für Digital Engineering GmbH, Penetrance, 030204 cardiovascular system & hematology, Ion Channels, 0302 clinical medicine, Bone Density, Loss of Function Mutation, Neoplasms, Databases, Genetic, Genetics research, Genotype, Exome, Exome sequencing, Biological Specimen Banks, education.field_of_study, Multidisciplinary, Genomics, Middle Aged, Biobank, Pedigree, Phenotype, ras GTPase-Activating Proteins, Female, Kidney Diseases, Population, Collagen Type VI, Computational biology, Biology, Article, DNA sequencing, Varicose Veins, 03 medical and health sciences, Exome Sequencing, Humans, education, Alleles, Aged, Demography, Rare variants, Peptide Fragments, United Kingdom, 030104 developmental biology, ddc:000, Next-generation sequencing
Abstract: The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community., Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Published: 2020
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22. Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease

Author: George Hindy, Lu-Chen Weng, Patrick T. Ellinor, Kumardeep Chaudhary, Phoebe Finneran, Girish N. Nadkarni, Anthony A. Philippakis, Amanda Dobbyn, Ruth J. F. Loos, Andrew Cagan, Jeffrey S. Reid, Renae Judy, Rachel L. Kember, Jordan W. Smoller, Amit Khera, Sekar Kathiresan, Daniel J. Rader, Scott T. Weiss, Aris Baras, John D. Overton, Krishna G. Aragam, Ron Do, Steven A. Lubitz, Pradeep Natarajan, Scott M. Damrauer, Mark Chaffin, Elizabeth W. Karlson, and Judy H. Cho
Subjects: Adult, Male, Multifactorial Inheritance, medicine.medical_specialty, Statin, Databases, Factual, medicine.drug_class, primary prevention, CAD, Coronary Artery Disease, 030204 cardiovascular system & hematology, genetic risk, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Primary prevention, Health care, medicine, Electronic Health Records, Humans, Genetic Predisposition to Disease, cardiovascular diseases, 030212 general & internal medicine, Genetic risk, Intensive care medicine, Aged, Aged, 80 and over, business.industry, statin, Disease Management, Guideline, Odds ratio, Middle Aged, medicine.disease, Practice Guidelines as Topic, Female, Cardiology and Cardiovascular Medicine, business, Delivery of Health Care
Abstract: Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by conventional paradigms for assessing clinical cardiovascular risk remains unclear.This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.
Published: 2020
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23. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Author: Jack A. Kosmicki, Charles Paulding, Nan Lin, Andrew J. Murphy, Jerome I. Rotter, Brian Zambrowicz, Niek Verweij, Luca A. Lotta, Michal L. Schwartzman, Giusy Della Gatta, Yii-Der Ida Chen, Alexander H. Li, Suganthi Balasubramanian, Jason M. Torres, Hyun Min Kang, Rory Collins, Parsa Akbari, Michael E. Dunn, Gonçalo R. Abecasis, Christian Benner, David J. Carey, Svati H. Shah, Jonathan Marchini, Giovanni Coppola, Marcus B. Jones, Olle Melander, Christopher D. Still, Yi-Ya Fang, Olukayode A. Sosina, Manuel A. R. Ferreira, Roberto Tapia-Conyer, Michael Cantor, Aris N. Economides, Dylan Sun, Adam E. Locke, Jonathan V. Pascale, Daniel J. Rader, Ankit Gilani, Joelle Mbatchou, Jesus Alegre-Díaz, Mark W. Sleeman, Trikaldarshi Persaud, Jeffrey G. Reid, Pablo Kuri-Morales, Jaime Berumen-Campos, John D. Overton, Aris Baras, Ercument Dirice, Sakib Hossain, Alicia Hawes, George D. Yancopoulos, Jonathan Emberson, Victor Garcia, Judith Altarejos, Lori Khrimian, Katia Karalis, William E. Kraus, Tooraj Mirshahi, Kevin Agostinucci, Alan R. Shuldiner, Center, Regeneron Genetics, and Collaboration, DiscovEHR
Subjects: 0301 basic medicine, Genetics, medicine.medical_specialty, Multidisciplinary, Body Weight, Genomics, Organ Size, Biology, medicine.disease, Obesity, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Genetic variation, medicine, Medical genetics, Humans, medicine.symptom, Body mass index, Weight gain, 030217 neurology & neurosurgery, Exome sequencing, Glycemic
Abstract: Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.
Published: 2022
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24. Classic Thrombophilias and Thrombotic Risk Among Middle-Aged and Older Adults: A Population-Based Cohort Study

Author: Eric Manderstedt, Christina Lind‐Halldén, Christer Halldén, Johan Elf, Peter J. Svensson, Björn Dahlbäck, Gunnar Engström, Olle Melander, Aris Baras, Luca A. Lotta, Bengt Zöller, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A Lotta, John D Overton, Jeffrey G Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Andrew Blumenfeld, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J Mansfield, Evan K Maxwell, Mrunali Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C Staples, Marcus B Jones, Jason Mighty, and Lyndon J Mitnaul
Subjects: Male, Anticoagulants, Factor V, Thrombosis, Venous Thromboembolism, Middle Aged, Antithrombins, Protein S, Cohort Studies, Risk Factors, RC666-701, Mutation, natural anticoagulants, Diseases of the circulatory (Cardiovascular) system, Humans, Thrombophilia, epidemiology, genetics, Female, Prothrombin, Cardiology and Cardiovascular Medicine, Aged, Protein C
Abstract: Background Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle‐aged and older adults. Methods and Results Factor V Leiden, prothrombin G20210A and protein‐coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease‐causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease‐causing mutations in the PROC , PROS1 , and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants. Conclusions The 5 classic thrombophilias are associated with a dose‐graded risk of VTE in middle‐aged and older adults. Disease‐causing variants in the PROC , PROS1 , and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.
Published: 2022

25. Association of thyroid function with blood pressure and cardiovascular disease: a mendelian randomization

Author: Alice Giontella, Luca A. Lotta, John D. Overton, Aris Baras, on behalf of Regeneron Genetics Center, Andrea Sartorio, Pietro Minuz, Dipender Gill, Olle Melander, and Cristiano Fava
Subjects: RISK, HYPERTHYROIDISM, endocrine system, Science & Technology, hypertension, endocrine system diseases, Medicine (miscellaneous), Article, thyroid, cardiovascular diseases, genetics, polymorphisms, Mendelian randomization, Health Care Sciences & Services, Medicine, General & Internal, HORMONE, General & Internal Medicine, ATRIAL-FIBRILLATION, Medicine, Life Sciences & Biomedicine
Abstract: Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.
Published: 2021

26. Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Author: Nehal Gosalia, Cristopher V. Van Hout, John D. Overton, Omri Gottesman, Ryan Murchie, Aris Baras, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Gabriel Welch, Aleixo M. Muise, Jeffrey G. Reid, Julie E. Horowitz, Karoline Fiedler, Neil Warner, Anne M. Griffiths, Alejandra King, Eileen Crowley, and Jeffrey Staples
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Science, Nod2 Signaling Adaptor Protein, Disease, Inflammatory bowel disease, Article, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Crohn Disease, NOD2, Immunogenetics, Medicine, Humans, Sequencing, Allele, Age of Onset, Child, Crohn's disease, Multidisciplinary, business.industry, Infant, Newborn, Infant, medicine.disease, Ulcerative colitis, digestive system diseases, 3. Good health, 030104 developmental biology, Child, Preschool, Immunology, Cohort, Mutation, Mendelian inheritance, symbols, 030211 gastroenterology & hepatology, Colitis, Ulcerative, Female, business, Medical genomics
Abstract: Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.
Published: 2021

27. THE CAUSAL ROLE OF SERUM CALCIUM, PTH AND FGF23 ON BLOOD PRESSURE: A TWO-SAMPLE MENDELIAN RANDOMIZATION

Author: Alice Giontella, Luca A. Lotta, John D. Overton, Aris Baras, Regeneron Genetics Center, Pietro Minuz, Olle Melander, and Cristiano Fava
Subjects: Physiology, Internal Medicine, Cardiology and Cardiovascular Medicine
Published: 2022
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28. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson
Subjects: Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published: 2021

29. ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers

Author: Xiaodong Bai, Dominique Monnet, Thierry Tabary, Carmelo Romano, Jack A. Kosmicki, Sahar Gelfman, Antoine P. Brézin, Eli A. Stahl, Manuel A. R. Ferreira, Jonathan Weyne, Aris Baras, Giovanni Coppola, Arden Moscati, Jacques H. M. Cohen, Blerta Cooper, Sarah Wolf, Ann J. Ligocki, Jan Freudenberg, and John D. Overton
Subjects: Heterozygote, Genotyping Techniques, HLA-A33, Human leukocyte antigen, Biology, ERAP1, Aminopeptidases, Polymorphism, Single Nucleotide, ERAP2, Minor Histocompatibility Antigens, Gene Frequency, Risk Factors, Genotype, medicine, Odds Ratio, Genetics, Humans, Genetic Predisposition to Disease, Allele, Allele frequency, Alleles, HLA-A Antigens, Haplotype, Birdshot Chorioretinopathy, Odds ratio, medicine.disease, Birdshot chorioretinopathy, birdshot, Haplotypes, HLA-Aw19, Cohort, Immunology, Expression quantitative trait loci, Multiplex Polymerase Chain Reaction, Genome-Wide Association Study
Abstract: PurposeBirdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.MethodsWe sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.ResultsCarrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, A30, A31, and A33) increases the risk for BSCR (OR=4.44, p=2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n=45,386, OR>2.5, pConclusionsThe genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2 specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.
Published: 2021

30. Thrombotic Risk Determined by STAB 2 Variants in a Population-Based Cohort Study

Author: Eric Manderstedt, Christer Halldén, Christina Lind-Halldén, Johan Elf, Peter J. Svensson, Gunnar Engström, Olle Melander, Aris Baras, Luca A Lotta, Bengt Zöller, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Katia Karalis, Katherine Siminovitch, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Andrew Blumenfeld, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mrunali Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C. Staples, Niek Verweij, Jonas Nielsen, Tanima De, Marcus B. Jones, Jason Mighty, Michelle G. LeBlanc, and Lyndon J. Mitnaul
Subjects: Thrombotic risk, medicine.medical_specialty, education.field_of_study, business.industry, Population, General Medicine, medicine.disease, Thrombosis, Population based cohort, Internal medicine, Medicine, business, education, Venous thromboembolism
Published: 2021
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31. Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial

Author: Sibylle Hess, Charles Paulding, Catherine Boileau, M. John Chapman, Luca A. Lotta, Garen Manvelian, George D. Yancopoulos, Michael Szarek, Gonçalo R. Abecasis, Emil Hagström, Aris Baras, Sotirios Tsimikas, Robert Pordy, Henry N. Ginsberg, Amy Damask, P. Gabriel Steg, Poulabi Banerjee, Gregory G. Schwartz, Lina Badimon, and John D. Overton
Subjects: Male, Multifactorial Inheritance, medicine.medical_specialty, polygenic inheritance, Hypercholesterolemia, Coronary Artery Disease, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Risk Factors, cardiovascular disease, Physiology (medical), Internal medicine, genomics, medicine, Humans, risk factors, genetics, cardiovascular diseases, subtilisin-kexin type 9, Aged, Proportional Hazards Models, 030304 developmental biology, Alirocumab, pharmacogenomics, 0303 health sciences, business.industry, Anticholesteremic Agents, PCSK9, PCSK9 Inhibitors, Cholesterol, LDL, Middle Aged, Placebo Effect, Proprotein convertase, medicine.disease, Cardiovascular Diseases, Pharmacogenomics, proprotein convertase, Kexin, Female, Polygenic risk score, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, Mace
Abstract: Background: Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile; P P =0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78–0.98]; P =0.022; interaction P =0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
Published: 2020
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32. A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant

Author: Orly Eshach Adiv, Liza Konnikova, Sarah Wall, Scott B. Snapper, Adi Mory, Dror S. Shouval, Ron Shaoul, Alina Kurolap, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Hagit Baris Feldman, Vanessa Mitsialis, Tamar Paperna, M. Steinberg, John D. Overton, Lael Werner, Moran Nunberg, and Yaniv Zohar
Subjects: Male, Models, Molecular, Candidate gene, Regulatory T cell, T cell, DNA Mutational Analysis, Immunology, Immunophenotyping, Structure-Activity Relationship, Immune system, Eosinophilia, Exome Sequencing, Eosinophilic, Humans, Immunology and Allergy, Medicine, Genetic Predisposition to Disease, Amino Acid Sequence, Age of Onset, Colitis, Child, Genetic Association Studies, Immunodeficiency, business.industry, Homozygote, Microfilament Proteins, medicine.disease, Immunohistochemistry, Ulcerative colitis, Enteritis, Phenotype, medicine.anatomical_structure, Child, Preschool, Gastritis, Mutation, business
Abstract: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient’s cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient’s innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.
Published: 2019
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33. Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations

Author: Zhongshan Cheng, Jeffrey S. Reid, Aris Baras, Ke Xu, William C. Becker, Philip S. Tsao, Daniel J. Rader, Derek Klarin, Scott M. Damrauer, Joel Gelernter, Renato Polimanti, Hang Zhou, Amy C. Justice, Hongyu Zhao, Henry R. Kranzler, John D. Overton, Rachel Vickers Smith, John Concato, Janet P. Tate, and Rachel L. Kember
Subjects: Adult, Male, 0301 basic medicine, Multifactorial Inheritance, Alcohol Drinking, Epidemiology, Science, Addiction, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Alcohol use disorder, Biology, Polymorphism, Single Nucleotide, Genome-wide association studies, Genetic correlation, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Genetics research, mental disorders, medicine, Humans, Longitudinal Studies, Risk factor, Young adult, Author Correction, lcsh:Science, Aged, Genetic association, Aged, 80 and over, Multidisciplinary, General Chemistry, Middle Aged, Heritability, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Alcoholism, Phenotype, 030104 developmental biology, Female, lcsh:Q, 0210 nano-technology, Genome-Wide Association Study, Demography
Abstract: Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits’ PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder., The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.
Published: 2019

34. A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4

Author: Alina Kurolap, Hagit Baris Feldman, John D. Overton, Ann Saada, Adi Mory, Tova Hershkovitz, Tamar Paperna, Sarah Wolf, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, and Hanna Mandel
Subjects: Male, 0301 basic medicine, Mitochondrial DNA, Mitochondrial Diseases, Mitochondrial disease, Disease, Oxidative phosphorylation, Peptide Elongation Factor Tu, 030105 genetics & heredity, Bioinformatics, DNA, Mitochondrial, Oxidative Phosphorylation, Mitochondrial Proteins, Consanguinity, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Missense mutation, Amino Acid Sequence, Genetics (clinical), business.industry, Homozygote, Infant, Dilated cardiomyopathy, medicine.disease, Phenotype, Mitochondria, 030104 developmental biology, Lactic acidosis, Mutation, Acidosis, Lactic, Female, Cardiomyopathies, business, Metabolism, Inborn Errors
Abstract: Translation of mitochondrial-specific DNA is required for proper mitochondrial function and energy production. For this purpose, an elaborate network of dedicated molecular machinery including initiation, elongation and termination factors exists. We describe a patient with an unusual phenotype and a novel homozygous missense variant in TUFM (c.344A>C; p.His115Pro), encoding mtDNA translation elongating factor Tu (EFTu). To date, only four patients have been reported with bi-allelic mutations in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis and progressive fatal infantile encephalopathy. The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy. This warrants the inclusion of TUFM in differential diagnosis of metabolic cardiomyopathy. Cases that further refine genotype-phenotype associations and characterize the molecular basis of mitochondrial disorders allow clinicians to predict disease prognosis, greatly impacting patient care, as well as provide families with reproductive planning options.
Published: 2019
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35. Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle‐aged and older adults: A population‐based cohort study

Author: Eric Manderstedt, Christina Lind‐Halldén, Christer Halldén, Johan Elf, Peter J. Svensson, Gunnar Engström, Olle Melander, Aris Baras, Luca A. Lotta, Bengt Zöller, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Andrew Blumenfeld, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mrunali Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Jason Mighty, and Lyndon J. Mitnaul
Subjects: Hematology
Abstract: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation.The genetic variation ofThe exomes ofNo common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2-7.1) for rare qualifying variants.Rare qualifying
Published: 2022
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36. Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Author: Martin I. Jones, Joseph D. Szustakowski, Giorgio Sirugo, Lukas Habegger, Adam J. Mansfield, Will Salerno, Joshua D. Backman, Athanasios Kousathanas, David J. Carey, Yi-Pin Lai, James F. Wilson, Alison M. Meynert, Anne E. Justice, Alexander H. Li, Jack A. Kosmicki, Anthony Marcketta, Sándor Szalma, Shane McCarthy, A. R. Shuldiner, A. Baras, Daniel J. Rader, Michael N. Cantor, Ashish Yadav, Manuel A. R. Ferreira, F. S. P. Kury, Konrad Rawlik, Loukas Moutsianas, Gonçalo R. Abecasis, Susan P. Walker, Xing Chen, Albert Tenesa, Paul Nioi, Adam E. Locke, Guillaume Butler-Laporte, E. N. Smith, Richard H Scott, Gundula Povysil, Joseph B. Leader, Lauren Gurski, Dorota Pasko, Marylyn D. Ritchie, A. Cordova-Palomera, Kyoko Watanabe, Colm O'Dushlaine, A. O'Neill, Tomoko Nakanishi, Erola Pairo-Castineira, Xiuwen Zheng, Emily Wong, Jeffrey G. Reid, Slavé Petrovski, Julie E. Horowitz, Anurag Verma, Justin W. Davis, Dylan Sun, Sahar Esmaeeli, Heiko Runz, Quanli Wang, John D. Overton, Shareef Khalid, Tooraj Mirshahi, Evan Maxwell, Mark J. Caulfield, Mark Lathrop, Olympe Chazara, Deepika Sharma, David Goldstein, Jonathan Marchini, Xiaodong Bai, Suganthi Balasubramanian, Krzysztof Kiryluk, Nilanjana Banerjee, Rouel Lanche, J. B. Richards, Hyun Min Kang, J. K. Baillie, Yunfeng Huang, Sean O'Keeffe, Erika Kvikstad, Margaret M. Parker, and Joelle Mbatchou
Subjects: Male, 0301 basic medicine, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Biology, 03 medical and health sciences, Current sample, 0302 clinical medicine, Data sequences, Report, Exome Sequencing, Genetics, Humans, Exome, Genetic Predisposition to Disease, 030212 general & internal medicine, Gene, Genetics (clinical), SARS-CoV-2, COVID-19, Prognosis, Hospitalization, 030104 developmental biology, Sample Size, Multiple comparisons problem, Susceptibility locus, Female, Interferons
Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.
Published: 2021
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37. Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

Author: Lukas Habegger, Max Orelus, Marcus B. Jones, Anurag Verma, Aris Economides, Shareef Khalid, William J Salerno, Adam J. Mansfield, Luca A. Lotta, Maria Sotiropoulos Padilla, Louis Widom, Michael Cantor, Giovanni Coppola, Katherine L. Nathanson, Suganthi Balasubramanian, Razvan Panea, John D. Overton, Alicia Hawes, Anh D. Le, Jeffrey C. Staples, Danielle L. Mowery, Jason Mighty, Kara N. Maxwell, Renae Judy, Andrew Blumenfeld, Manasi Pradhan, Peter Gabriel, Heena Desai, Caitlin Forsythe, Jeffrey G. Reid, Lyndon J. Mitnaul, Christina Beechert, Xiaodong Bai, Olga Krasheninina, Zhenhua Gu, Abigail Doucette, Mrunali Nafde, Boris Boutkov, Kia Manoochehri, Marylyn D. Ritchie, Tommy Polanco, Rouel Lanche, Alexander E. Lopez, Ryan Hausler, Alan R. Shuldiner, Sarah E. Wolf, Thomas D. Schleicher, Gisu Eom, Shefali S. Verma, Sean O’Keeffe, Ayesha Rasool, Rachel L. Kember, Evan Maxwell, Michael Lattari, Erin D. Fuller, Scott M. Damrauer, Ricardo H. Ulloa, Gonçalo R. Abecasis, Louise Wang, and Aris Baras
Subjects: Gerontology, business.industry, Medicine, Cancer, Polygenic risk score, business, medicine.disease, Biobank
Abstract: PurposeGenome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) significantly associated with several cancers, but the predictive ability of polygenic risk scores (PRS) is unclear, especially among non-Whites.MethodsGenome-wide genotype data was available for 20,079 individuals enrolled in an academic biobank. PRS were derived from significant DNA variants for 15 cancers. We determined the discriminatory accuracy of each cancer-specific PRS in patients of genetically-determined African and European ancestry separately.ResultsAmong individuals of European genetic ancestry, PRS for breast, colon, melanoma, and prostate were significantly associated with their respective cancers (OR 1.25-1.47). Among individuals of African genetic ancestry, PRS for breast, colon, and prostate were significantly associated with their respective cancers. The AUC of a model comprised of age, sex, and principal components was 0.617–0.709 and increased by 1-4% with the PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, AUC was overall higher in the model without PRS (0.740-0.811) but increased < 1% with the PRS in the majority of cancers.ConclusionPRS constructed from SNPs moderately increased discriminatory ability for cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.
Published: 2021
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38. Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

Author: Louise Wang, Heena Desai, Shefali S. Verma, Anh Le, Ryan Hausler, Anurag Verma, Renae Judy, Abigail Doucette, Peter E. Gabriel, Katherine L. Nathanson, Scott M. Damrauer, Danielle L. Mowery, Marylyn D. Ritchie, Rachel L. Kember, Kara N. Maxwell, Goncalo Abecasis, Xiaodong Bai, Suganthi Balasubramanian, Aris Baras, Andrew Blumenfeld, Boris Boutkov, Michael Cantor, Giovanni Coppola, Aris Economides, Gisu Eom, Lukas Habegger, Alicia Hawes, Marcus B. Jones, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Luca A. Lotta, Adam J. Mansfield, Evan K. Maxwell, Jason Mighty, Lyndon J. Mitnaul, Mrunali Nafde, Sean O’Keeffe, Max Orelus, John D. Overton, Razvan Panea, Tommy Polanco, Ayesha Rasool, Jeffrey G. Reid, William Salerno, Jeffrey C. Staples, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Kia Manoochehri, Manasi Pradhan, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Ricardo H. Ulloa, Louis Widom, and Sarah E. Wolf
Subjects: Male, Multifactorial Inheritance, Risk Factors, Neoplasms, Black People, Humans, Female, Genetic Predisposition to Disease, Genetics (clinical), White People, Biological Specimen Banks, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites.PRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry.Among the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by1% with the inclusion of PRS for most cancers.PRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.
Published: 2021

39. Within-sibship GWAS improve estimates of direct genetic effects

Author: Ailin Falkmo Hansen, Christina C. Dahm, David M. Evans, Massimo Mangino, Melissa C. Southey, Lawrence F. Bielak, Ben Michael Brumpton, Sharon L.R. Kardia, Archie Campbell, Yoonsu Cho, Tim T Morris, Patrick Turley, Jeffrey S. Reid, Laurence J. Howe, Kaare Christensen, Karri Silventoinen, Sudheer Giddaluru, John K. Hewitt, Philipp Koellinger, W. David Hill, Daniel J. Benjamin, Gibran Hemani, Margaret J. Wright, Scott D. Gordon, Elliot M. Tucker-Drob, Rosa Cheesman, Nicholas G. Martin, Robin G. Walters, Paraskevi Christofidou, Aris Baras, George Davey Smith, Matthew C. Keller, John D. Overton, Deepika R Dokuru, Jennifer A. Smith, Nancy L. Pedersen, Michel G. Nivard, Dorret I. Boomsma, Jaakko Kaprio, Humaira Rasheed, Hyeokmoon Kweon, Sara Hägg, Shona M. Kerr, John L. Hopper, Pekka Martikainen, Teemu Palviainen, Luke M. Evans, Patricia A. Peyser, Jared V. Balbona, Lucija Klaric, Tim D. Spector, Patrik K. E. Magnusson, Melinda Mills, Alexandra Havdahl, Chandra A. Reynolds, Jean-Baptiste Pingault, Zhengming Chen, Shuai Li, Harry Campbell, Travis T. Mallard, Cristen J. Willer, Yunzhang Wang, Yongkang Kim, Robert Plomin, Marianne Nygaard, Michael C. Stallings, Sarah E. Medland, Anne E. Justice, Geetha Chittoor, Debbie A Lawlor, Øyvind Næss, Liming Li, Kuang Lin, Eco J. C. de Geus, Christopher R. Bauer, Matthijs D. van der Zee, Iona Y Millwood, Caroline Hayward, Penelope A. Lind, David J. Porteous, K. Paige Harden, Meike Bartels, Neil M Davies, James F. Wilson, Bjørn Olav Åsvold, Antti Latvala, Scott M. Ratliff, and Kristian Hveem
Subjects: 0303 health sciences, education.field_of_study, Assortative mating, Population, Genome-wide association study, Biology, Population stratification, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Genetic variation, Mendelian randomization, Human height, education, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects, but large-scale family datasets have been lacking. We combined data on 159,701 siblings from 17 cohorts to generate population (between-family) and within-sibship (within-family) estimates of genome-wide genetic associations for 25 phenotypes. We demonstrate that existing GWAS associations for height, educational attainment, smoking, depressive symptoms, age at first birth and cognitive ability overestimate direct effects. We show that estimates of SNP-heritability, genetic correlations and Mendelian randomization involving these phenotypes substantially differ when calculated using within-sibship estimates. For example, genetic correlations between educational attainment and height largely disappear. In contrast, analyses of most clinical phenotypes (e.g. LDL-cholesterol) were generally consistent between population and within-sibship models. We also report compelling evidence of polygenic adaptation on taller human height using within-sibship data. Large-scale family datasets provide new opportunities to quantify direct effects of genetic variation on human traits and diseases.
Published: 2021
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40. Kidney disease genetic risk variants alter lysosomal beta-mannosidase ( MANBA ) expression and disease severity

Author: Christopher D. Brown, Yi-An Ko, Adriana M. Hung, Marylyn D. Ritchie, Jeffrey S. Reid, Ishan Paranjpe, Ruth J. F. Loos, Scott M. Damrauer, Shizheng Huang, Xin Sheng, John D. Overton, Xiangchen Gu, Renae Judy, Jihwan Park, Aris Baras, Hongliu Yang, Girish N. Nadkarni, Daniel J. Rader, Chengxiang Qiu, Kumardeep Chaudhary, Katalin Susztak, Joseph Park, Aparna Saha, Erwin P. Bottinger, Shreeram Akilesh, Rachel L. Kember, Vy Thi Ha My, and Matthew Palmer
Subjects: medicine.medical_specialty, Kidney, Beta-mannosidase, Genome-wide association study, General Medicine, Biology, medicine.disease, medicine.anatomical_structure, Genotype, Immunology, medicine, Medical genetics, Exome sequencing, Genetic association, Kidney disease
Abstract: More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney–specific expression quantitative trait analysis and identified that the expression of beta-mannosidase (MANBA) was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in MANBA using phenome-wide association analysis of 40,963 subjects with exome sequencing data. MANBA is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of Manba. Manba heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. Manba loss altered multiple pathways, including endocytosis and autophagy. In the absence of Manba, toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in MANBA in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.
Published: 2021
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41. Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations

Author: Manuel A. R. Ferreira, Ali Naji, Todd L. Edwards, Anne E. Justice, Marylyn D. Ritchie, John D. Overton, Theodore G. Drivas, Nathan Katz, Ying H. Shen, Yanming Li, Renae Judy, Anastasia Lucas, Amanda Dobbyn, Anurag Verma, Scott M. Damrauer, Daniel J. Rader, Geetha Chittoor, Maria Fasolino, Xinyuan Zhang, Jinbo Chen, Scott A. LeMaire, Alexander H. Li, Joseph H. Breeyear, Rachel L. Kember, Kumardeep Chaudhary, Joseph Park, JoEllen Weaver, Shadi Ahmadmehrabi, Alan Daugherty, Hisashi Sawada, Yuki Bradford, Klaus H. Kaestner, Jeffrey G. Reid, Ron Do, Navya Shilpa Josyula, Golnaz Vahedi, Girish N. Nadkarni, Judy H. Cho, Chen Zhang, Aris Baras, and Venkata R M Chavali
Subjects: 0301 basic medicine, Male, Genotype, Population, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Exome Sequencing, Electronic Health Records, Humans, Exome, education, Exome sequencing, Aged, Genetics, education.field_of_study, Computational Biology, General Medicine, Biobank, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Genome-Wide Association Study
Abstract: The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P
Published: 2021

42. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author: Lukas Habegger, Charumathi Sabanayagam, Michael Preuss, Laura M. Raffield, Mary F. Feitosa, Bamidele O. Tayo, Kevin Ho, Leo-Pekka Lyytikäinen, Florian Kronenberg, Valencia Hui Xian Foo, Adrienne Tin, Michael Cantor, Nisha Bansal, Tarunveer S. Ahluwalia, Melanie Waldenberger, Sarah A. Pendergrass, Behrooz Z. Alizadeh, Wolfgang Koenig, Qiong Yang, Xiaodong Bai, Christoph Wanner, Ben Schöttker, Giovanni Coppola, A. R. Shuldiner, Leslie A. Lange, Piyush Gampawar, Markus Scholz, Tien Yin Wong, Mary L. Biggs, Morris Swertz, Alicia Hawes, Girish N. Nadkarni, Christina-Alexandra Schulz, Chiea Chuen Khor, Ricardo H. Ulloa, Jeffrey C. Staples, Miao-Li Chee, Laura M. Yerges-Armstrong, Andrew Blumenfeld, Karlhans Endlich, Bernhard Banas, Bruce H.R. Wolffenbuttel, Kai-Uwe Eckardt, Pavel Hamet, Carsten A. Böger, Harold Snieder, Marcus B. Jones, Judy Wang, Shih-Jen Hwang, Mathias Gorski, Anselm Hoppmann, Josyf C. Mychaleckyj, Bernd Holleczek, Pamela R. Matias-Garcia, Rainer Rettig, Karsten B. Sieber, Manasi Pradhan, Pashupati P. Mishra, Peter Rossing, Matthias Wuttke, Miao-Ling Chee, H. Marike Boezen, Yong Li, M. Arfan Ikram, Jeffrey G. Reid, Teresa Nutile, Maria Sotiropoulos Padilla, Lude Franke, Robert J. Carroll, Luca A. Lotta, Bernhard K. Krämer, Kjell Nikus, Jerome I. Rotter, Thomas Meitinger, Lars Wallentin, Cisca Wijmenga, Kent D. Taylor, Holly Kramer, Louis Widom, Olli T. Raitakari, Marcus E. Kleber, Man Li, Nina Hutri-Kähönen, Massimiliano Cocca, Reinhold Schmidt, John D. Overton, Cristian Pattaro, Michael Lattari, Sarah E. Wolf, Jin-Fang Chai, Karina Toledo, Brigitte Kühnel, Zhenhua Gu, Peter Almgren, Caitlin Forsythe, Yuri Milaneschi, Stephan J. L. Bakker, Layal Chaker, Dawn M. Waterworth, Silke Szymczak, James G. Wilson, Peter J. van der Most, Michelle L. O'Donoghue, William Salerno, Masayuki Yasuda, Sahar Ghasemi, Eric Boerwinkle, Josef Coresh, Ilja M. Nolte, Kia Manoochehri, Konstantin Strauch, Thomas D. Schleicher, Myriam Rheinberger, Audrey Y. Chu, Sanaz Sedaghat, Sandra Freitag-Wolf, Boting Ning, Matthias Nauck, Christina Beechert, Helena Schmidt, Harvey D. White, Nina Mononen, Johanne Tremblay, Navya Shilpa Josyula, Mika Kähönen, Katrin Horn, Andre Franke, Marianne Rots, Bettina Jung, Alexander R. Rosenkranz, Christian M. Shaffer, Mary Ann Lukas, Gerjan Navis, Christian Gieger, John Chalmers, Shareef Khalid, Uwe Völker, Marju Orho-Melander, Iris M. Heid, Brenda W.J.H. Penninx, A. Baras, Alexander Lopez, Evan Maxwell, Ruth J. F. Loos, Erin D. Fuller, Christa Meisinger, Gonçalo R. Abecasis, Suganthi Balasubramanian, Chris H. L. Thio, Martin H. de Borst, Stefan Coassin, Ching-Yu Cheng, Wolfgang Lieb, Kenneth Rice, Alexander Teumer, Mark Woodward, Gisu Eom, Hermann Brenner, Thomas W. Winkler, Anna Köttgen, Edith Hofer, Aris Economides, Ron T. Gansevoort, Pim van der Harst, Lyndon J. Mitnaul, Bruce M. Psaty, Erwin P. Bottinger, Olle Melander, Niek Verweij, Frauke Degenhardt, Yan Zhang, Mohsen Ghanbari, Veronika Wanner, Terho Lehtimäki, Leland Barnard, Tampere University, Primary Health Care, Department of Paediatrics, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Department of Marketing Management, Epidemiology, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health
Subjects: 0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19
Published: 2021
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43. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. 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A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. 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S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., 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Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .
Subjects: Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract: [BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.
Published: 2021

44. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Author: Cindy G. Boer, Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefánsdóttir, Yanfei Zhang, Rodrigo Coutinho de Almeida, Tian T. Wu, Jie Zheng, April Hartley, Maris Teder-Laving, Anne Heidi Skogholt, Chikashi Terao, Eleni Zengini, George Alexiadis, Andrei Barysenka, Gyda Bjornsdottir, Maiken E. Gabrielsen, Arthur Gilly, Thorvaldur Ingvarsson, Marianne B. Johnsen, Helgi Jonsson, Margreet Kloppenburg, Almut Luetge, Sigrun H. Lund, Reedik Mägi, Massimo Mangino, Rob R.G.H.H. Nelissen, Manu Shivakumar, Julia Steinberg, Hiroshi Takuwa, Laurent F. Thomas, Margo Tuerlings, George C. Babis, Jason Pui Yin Cheung, Jae Hee Kang, Peter Kraft, Steven A. Lietman, Dino Samartzis, P. Eline Slagboom, Kari Stefansson, Unnur Thorsteinsdottir, Jonathan H. Tobias, André G. Uitterlinden, Bendik Winsvold, John-Anker Zwart, George Davey Smith, Pak Chung Sham, Gudmar Thorleifsson, Tom R. Gaunt, Andrew P. Morris, Ana M. Valdes, Aspasia Tsezou, Kathryn S.E. Cheah, Shiro Ikegawa, Kristian Hveem, Tõnu Esko, J. Mark Wilkinson, Ingrid Meulenbelt, Ming Ta Michael Lee, Joyce B.J. van Meurs, Unnur Styrkársdóttir, Eleftheria Zeggini, John Loughlin, Nigel Arden, Fraser Birrell, Andrew Carr, Panos Deloukas, Michael Doherty, Andrew W. McCaskie, William E.R. Ollier, Ashok Rai, Stuart H. Ralston, Tim D. Spector, Gillian A. Wallis, Amy E. Martinsen, Cristen Willer, Egil Andreas Fors, Ingunn Mundal, Knut Hagen, Kristian Bernhard Nilsen, Marie Udnesseter Lie, Sigrid Børte, Ben Brumpton, Jonas Bille Nielsen, Lars G. Fritsche, Wei Zhou, Ingrid Heuch, Kjersti Storheim, Evangelos Tyrpenou, Athanasios Koukakis, Dimitrios Chytas, Dimitrios Stergios Evangelopoulos, Chronopoulos Efstathios, Spiros Pneumaticos, Vasileios S. Nikolaou, Konstantinos Malizos, Lydia Anastasopoulou, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Katia Karalis, Katherine Siminovitch, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Xiaodong Bai, Suganthi Balasubramanian, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey C. Staples, Dadong Li, Deepika Sharma, Ilanjana Banerjee, Jonas Bovijn, Adam Locke, Niek Verweij, Mary Haas, George Hindy, Tanima De, Parsa Akbari, Olukayode Sosina, Manuel A.R. Ferreira, Marcus B. Jones, Jason Mighty, Michelle G. LeBlanc, Lyndon J. Mitnaul, and Internal Medicine
Subjects: Resource, genome-wide association meta-analysis, Disease, Osteoarthritis, effector genes, Biology, Bioinformatics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Drug Targets, Effector Genes, Functional Genomics, Genetic Architecture, Genome-wide Association Meta-analysis, Spine osteoarthritis, Risk Factors, drug targets, medicine, Humans, Genetic Predisposition to Disease, Sex Characteristics, Cartilage, Correction, medicine.disease, Phenotype, genetic architecture, Genetic architecture, ddc, osteoarthritis, Genetics, Population, medicine.anatomical_structure, Subchondral bone, Female, Functional genomics, functional genomics, Genome-Wide Association Study, Signal Transduction
Abstract: Summary Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation., Graphical abstract, Highlights • A multicohort study identifies 52 previously unknown osteoarthritis genetic risk variants • Similarities and differences in osteoarthritis genetic risk depend on joint sites • Osteoarthritis genetic components are associated with pain-related phenotypes • High-confidence effector genes highlight potential targets for drug intervention, A multicohort genome-wide association meta-analysis of osteoarthritis highlights the impact of joint site types on the features of genetic risk variants and the link between osteoarthritis genetics and pain-related phenotypes, pointing toward potential targets for therapeutic intervention.
Published: 2021
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45. Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Author: Marie V. Coignet, Dylan Sun, Lukas Habegger, Evan Maxwell, Daniel J. Rader, David J. Carey, Katherine A. Siminovitch, Giorgio Sirugo, Anne E. Justice, Joelle Mbatchou, Eli A. Stahl, Gonçalo R. Abecasis, Alexander H. Li, David A. Turissini, Adam E. Locke, Kristin A. Rand, Aris Baras, Joseph B. Leader, Genevieve H.L. Roberts, Ahna R. Girshick, Deepika Sharma, Nilanjana Banerjee, Fabricio S. P. Kury, John D. Overton, Shane McCarthy, Jonathan Marchini, Xiaodong Bai, Eurie L. Hong, Rouel Lanche, Amy Damask, Ashish Yadav, Raghavendran Partha, Shannon R. McCurdy, Miao Zhang, Suganthi Balasubramanian, Hyun Min Kang, Anurag Verma, Marcus B. Jones, Marylyn D. Ritchie, Colm O'Dushlaine, Manuel A. R. Ferreira, Adam J. Mansfield, Anthony Marcketta, Joshua D. Backman, Alan R. Shuldiner, Michael N. Cantor, Tooraj Mirshahi, Lee Dobbyn, Spencer C. Knight, William J Salerno, Harenda Guturu, Jeffrey G. Reid, Julie E. Horowitz, Lauren Gurski, Danny S. Park, Kyoko Watanabe, Catherine A. Ball, Asher K. Haug Baltzell, and Jack A. Kosmicki
Subjects: 2019-20 coronavirus outbreak, Increased risk, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Genetic variants, MEDLINE, Severe disease, Medicine, Bioinformatics, business
Abstract: SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.
Published: 2020
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46. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank

Author: Joseph D, Szustakowski, Suganthi, Balasubramanian, Erika, Kvikstad, Shareef, Khalid, Paola G, Bronson, Ariella, Sasson, Emily, Wong, Daren, Liu, J, Wade Davis, Carolina, Haefliger, A, Katrina Loomis, Rajesh, Mikkilineni, Hyun Ji, Noh, Samir, Wadhawan, Xiaodong, Bai, Alicia, Hawes, Olga, Krasheninina, Ricardo, Ulloa, Alex E, Lopez, Erin N, Smith, Jeffrey F, Waring, Christopher D, Whelan, Ellen A, Tsai, John D, Overton, William J, Salerno, Howard, Jacob, Sandor, Szalma, Heiko, Runz, Gregory, Hinkle, Paul, Nioi, Slavé, Petrovski, Melissa R, Miller, Aris, Baras, Lyndon J, Mitnaul, Jeffrey G, Reid, and Zhan, Ye
Subjects: Research, Drug Discovery, Exome Sequencing, Humans, Human Genetics, Genomics, United Kingdom, Biological Specimen Banks
Abstract: The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a private-public partnership between the UK Biobank (UKB) and eight biopharmaceutical companies that will complete the sequencing of exomes for all ~500,000 UKB participants. Here, we describe the early results from ~200,000 UKB participants and the features of this project that enabled its success. The biopharmaceutical industry has increasingly used human genetics to improve success in drug discovery. Recognizing the need for large-scale human genetics data, as well as the unique value of the data access and contribution terms of the UKB, the UKB-ESC was formed. As a result, exome data from 200,643 UKB enrollees are now available. These data include ~10 million exonic variants-a rich resource of rare coding variation that is particularly valuable for drug discovery. The UKB-ESC precompetitive collaboration has further strengthened academic and industry ties and has provided teams with an opportunity to interact with and learn from the wider research community.
Published: 2020

47. Advancing Human Genetics Research and Drug Discovery through Exome Sequencing of the UK Biobank

Author: Xiaodong Bai, Samir Wadhawan, Howard J. Jacob, Carolina Haefliger, Ariella Sasson, Rajesh Mikkilineni, Daren Liu, William J. Salerno, Jeffrey F. Waring, Joseph D. Szustakowski, Emily Wong, Paola G. Bronson, Ellen A. Tsai, Gregory Hinkle, Suganthi Balasubramanian, Alex Lopez, Olga Krasheninina, A. Katrina Loomis, E. N. Smith, Melissa R. Miller, Sándor Szalma, Hyun Ji Noh, Heiko Runz, Paul Nioi, Shareef Khalid, Christopher D. Whelan, Jeffrey G. Reid, Slavé Petrovski, Alicia Hawes, Lyndon J. Mitnaul, Ricardo Ulloa, John D. Overton, J. Wade Davis, Aris Baras, and Erika Kvikstad
Subjects: 0303 health sciences, business.industry, Drug discovery, Genomics, Computational biology, Biology, Data science, Biobank, Human genetics, 03 medical and health sciences, Open data, 0302 clinical medicine, Drug development, General partnership, Genetics, business, Indel, Exome, 030217 neurology & neurosurgery, Biomedicine, Exome sequencing, 030304 developmental biology
Abstract: The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a unique private/public partnership between the UK Biobank and eight biopharma companies that will sequence the exomes of all ∼500,000 UK Biobank participants. Here we describe early results from the exome sequence data generated by this consortium for the first ∼200,000 UKB subjects and the key features of this project that enabled the UKB-ESC to come together and generate this data.Exome sequencing data from the first 200,643 UKB enrollees are now accessible to the research community. Approximately 10M variants were observed within the targeted regions, including: 8,086,176 SNPs, 370,958 indels and 1,596,984 multi-allelic variants. Of the ∼8M variants observed, 84.5% are coding variants and include 2,139,318 (25.3%) synonymous, 4,549,694 (53.8%) missense, 453,733 (5.4%) predicted loss-of-function (LOF) variants (initiation codon loss, premature stop codons, stop codon loss, splicing and frameshift variants) affecting at least one coding transcript. This open access data provides a rich resource of coding variants for rare variant genetic studies, and is particularly valuable for drug discovery efforts that utilize rare, functionally consequential variants.Over the past decade, the biopharma industry has increasingly leveraged human genetics as part of their drug discovery and development strategies. This shift was motivated by technical advances that enabled cost-effective human genetics research at scale, the emergence of electronic health records and biobanks, and a maturing understanding of how human genetics can increase the probability of successful drug development. Recognizing the need for large-scale human genetics data to drive drug discovery, and the unique value of the open data access policies and contribution terms of the UK Biobank, the UKB-ESC was formed. This precompetitive collaboration has further strengthened the ties between academia and industry and provided teams an unprecedented opportunity to interact with and learn from the wider research community.
Published: 2020
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48. A catalog of associations between rare coding variants and COVID-19 outcomes

Author: Anurag Verma, Anne E. Justice, Guillaume Butler-Laporte, E. N. Smith, Lukas Habegger, Joelle Mbatchou, Susan P. Walker, Albert Tenesa, Joseph D. Szustakowski, Konrad Rawlik, Dylan Sun, Loukas Moutsianas, Shane McCarthy, Richard H Scott, Aris Baras, Evan Maxwell, Aldo Cordova-Palomera, Tooraj Mirshahi, Dorota Pasko, David J. Carey, Sahar Esmaeli, Adam J. Mansfield, Quanli Wang, Jeffrey S. Reid, Nilanjana Banerjee, Joshua D. Backman, Athanasios Kousathanas, Ashish Yadav, Mark J. Caulfield, Alison M. Meynert, Rouel Lanche, Jack A. Kosmicki, James F. Wilson, J. Brent Richards, Heiko Runz, Gonçalo R. Abecasis, Adam E. Locke, Justin W. Davis, Mark Lathrop, Alan R. Shuldiner, Lauren Gurski, J Kenneth Baillie, Michael N. Cantor, David Goldstein, John D. Overton, Kyoko Watanabe, Amanda O'Neill, Yunfeng Huang, Jonathan Marchini, Xiaodong Bai, Krzysztof Kiryluk, Slavé Petrovski, Sean O'Keeffe, Erika Kvikstad, Anthony Marcketta, Margaret M. Parker, Giorgio Sirugo, Julie E. Horowitz, Emily Wong, Olympe Chazara, Paul Nioi, Manuel A. R. Ferreira, Sándor Szalma, Joseph B. Leader, Shareef Khalid, William J Salerno, Deepika Sharma, Tomoko Nakanishi, Marcus B. Jones, Gundula Povysil, Marylyn D. Ritchie, Colm O'Dushlaine, Xiuwen Zheng, Daniel J. Rader, Suganthi Balasubramanian, Hyun Min Kang, Yi-Pin Lai, Alexander H. Li, Xing Chen, and Erola Pairo-Castineira
Subjects: Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Genome-wide association study, medicine.disease_cause, Biobank, Article, Genetic association analysis, Immunology, Multiple comparisons problem, Medicine, business, Gene, Coronavirus
Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable athttps://rgc-covid19.regeneron.com.
Published: 2020
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49. Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Author: Marylyn D. Ritchie, Colm O'Dushlaine, Aris Baras, Jeffrey D. Reid, Sofiya Milman, Alan R. Shuldiner, Patrick Sin-Chan, Dadong Li, Scott M. Damrauer, David J. Carey, David H. Ledbetter, Nir Barzilai, Cristopher V. Van Hout, David J. Glass, Anthony Marcketta, Nehal Gosalia, Aris N. Economides, Daniel J. Rader, Alexander H. Li, Bin Ye, John D. Overton, and Chuan Gao
Subjects: Genetics, Germline mutation, Cohort, Epigenetics, Biology, Exome, Gene, Exome sequencing, Ashkenazi jews, Genetic association
Abstract: SUMMARYAging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40×10−10) and ZYG11A rs74227999 (p = 2.50×10−08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males ≥ 92 years, Females ≥ 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.
Published: 2020
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50. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease

Author: Karlla W. Brigatti, John D. Overton, Mark Yoder, Anthony Antonellis, Vincent J Carson, Erick D Martinez, Lili Miles, Kadakkal Radhakrishnan, Vinay Kandula, Aris Baras, Claudia Gonzaga-Jauregui, Laurie B. Griffin, Jeffrey G. Reid, Robert N. Jinks, Erik G. Puffenberger, Katie B. Williams, Katryn N. Furuya, Olivia Wenger, Kevin A. Strauss, Matthew M Demczko, Laura Poskitt, and Michael D Fox
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Hearing Loss, Sensorineural, 030105 genetics & heredity, Biology, Hypoglycemia, medicine.disease_cause, Severity of Illness Index, 03 medical and health sciences, Loss of Function Mutation, Tyrosine-tRNA Ligase, Catalytic Domain, Yeasts, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Exome sequencing, Mutation, Homozygote, Genetic Diseases, Inborn, Infant, Newborn, Infant, Heterozygote advantage, General Medicine, medicine.disease, Pedigree, Complementation, Phenotype, Peripheral neuropathy, Child, Preschool, Female, Sensorineural hearing loss, General Article
Abstract: Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.
Published: 2018
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