Person: Bick, Alexander
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Bick
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Alexander
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Bick, Alexander
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Publication Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease(Nature Publishing Group UK, 2018) Emdin, Connor; Khera, Amit; Chaffin, Mark; Klarin, Derek; Natarajan, Pradeep; Aragam, Krishna; Haas, Mary; Bick, Alexander; Zekavat, Seyedeh M.; Nomura, Akihiro; Ardissino, Diego; Wilson, James G.; Schunkert, Heribert; McPherson, Ruth; Watkins, Hugh; Elosua, Roberto; Bown, Matthew J.; Samani, Nilesh J.; Baber, Usman; Erdmann, Jeanette; Gupta, Namrata; Danesh, John; Chasman, Daniel; Ridker, Paul; Denny, Joshua; Bastarache, Lisa; Lichtman, Judith H.; D’Onofrio, Gail; Mattera, Jennifer; Spertus, John A.; Sheu, Wayne H.-H.; Taylor, Kent D.; Psaty, Bruce M.; Rich, Stephen S.; Post, Wendy; Rotter, Jerome I.; Chen, Yii-Der Ida; Krumholz, Harlan; Saleheen, Danish; Gabriel, Stacey; Kathiresan, SekarLess than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.Publication At the Heart of the Genome: Rare Genetic Variation, Cardiovascular Disease, and Therapy(2014-06-06) Bick, Alexander; Seidman, Jonathan G.; Seidman, Christine Edry; Daly, Mark; Warman, Matthew; Huggins, Gordon; Michel, ThomasStudies of large families with inherited single gene disorders identified a role of rare genetic variation as a cause of disease and enabled gene-based diagnosis. The increasing availability of population-scale genomic sequencing implies the potential to extend gene-based diagnosis from individuals with monogenic disease to the prediction of disease risk in the general population. Cardiovascular disease (CVD), as a highly heritable condition with significant public health burden, represents an excellent place to consider the promise and limitations of extending our understanding of rare variation in single gene disorders to the general population.Publication Evolutionary Diversity of the Mitochondrial Calcium Uniporter and Its Contribution to Cardiac and Vascular Homeostasis(2016-05-17) Bick, AlexanderAltered cardiac energetics and calcium handling are characteristic features of cardiovascular disease. Mitochondria play a significant role in both cellular energy generation and calcium homeostasis and may be a key integration point of these two systems. Calcium uptake into mitochondria occurs via a recently identified mitochondrial calcium uniporter complex. In the first part of this thesis, I characterize the phylogenomic distribution of the uniporter’s membrane spanning pore (MCU) and regulatory subunits (MICU1 and MICU2). Homologs of both MCU and MICU1 tend to co-occur in all major branches of eukaryotic life but both have been lost along certain protozoan and fungal lineages. MICU2 represents a recent duplication of MICU1. Several bacterial genomes also contain putative MCU homologs that may represent prokaryotic calcium channels. The analyses indicate that the uniporter may have been an early feature of mitochondria. In the second part of this thesis, I perform transcriptome wide analysis of human and mouse cardiomyopathy datasets and identify MICU2, a regulatory component of the mitochondrial calcium uniporter, as one of six genes consistently upregulated in cardiac disease states. I test the hypothesis that increased MICU2 expression is cardio-protective by generating a global Micu2-/- mouse. These mice have diastolic dysfunction. Isolated Micu2-/- cardiomyocytes show altered sarcomere relaxation and cytosolic calcium reuptake kinetics and Micu2-/- ventricular tissue has transcriptional dysregulation of genes encoding sarcomere proteins and bZIP transcription factors. When exposed to two weeks of angiotensin 2, a pharmacologic hypertrophic stimuli, Micu2-/- mice exhibit both systolic and diastolic dysfunction. Together, these data point to a significant and previously unappreciated role for Micu2 in maintaining both cardiac and vascular homeostasis.Publication Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter(National Academy of Sciences, 2017) Bick, Alexander; Wakimoto, Hiroko; Kamer, Kimberli; Sancak, Yasemin; Goldberger, Olga; Axelsson, Anna; DeLaughter, Daniel; Gorham, Joshua; Mootha, Vamsi; Seidman, J. G.; Seidman, ChristineComparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2−/− mice. Mutant mice had left atrial enlargement and Micu2−/− cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2−/− ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (Micu2−/− vs. wild type, P = 7.8 × 10−40), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that Micu2−/− and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that Micu2−/− mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from Micu2−/− mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that Micu2−/− mice recapitulate features of diastolic heart disease and define previously unappreciated roles for Micu2 in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.Publication Inherited Causes of Clonal Haematopoiesis in 97,691 Whole Genomes(Springer Science and Business Media LLC, 2020-10-14) Bick, Alexander; Weinstock, Joshua S.; Nandakumar, Satish K.; Fulco, Charles P.; Bao, Erik; Zekavat, Seyedeh M.; Szeto, Mindy D.; Liao, Xiaotian; Leventhal, Matthew J.; Nasser, Joseph; Chang, Kyle; Laurie, Cecelia; Burugula, Bala Bharathi; Gibson, Christopher J.; Niroula, Abhishek; Lin, Amy; Taub, Margaret A.; Aguet, Francois; Ardlie, Kristin; Mitchell, Braxton D.; Barnes, Kathleen C.; Moscati, Arden; Fornage, Myriam; Redline, Susan; Psaty, Bruce M.; Silverman, Edwin; Weiss, Scott; Palmer, Nicholette D.; Vasan, Ramachandran S.; Burchard, Esteban G.; Kardia, Sharon L. R.; He, Jiang; Kaplan, Robert C.; Smith, Nicholas L.; Arnett, Donna K.; Schwartz, David A.; Correa, Adolfo; de Andrade, Mariza; Guo, Xiuqing; Konkle, Barbara A.; Custer, Brian; Peralta, Juan M.; Gui, Hongsheng; Meyers, Deborah A.; McGarvey, Stephen T.; Chen, Ida Yii-Der; Shoemaker, M. Benjamin; Peyser, Patricia A.; Broome, Jai G.; Gogarten, Stephanie M.; Wang, Fei Fei; Wong, Quenna; Montasser, May E.; Daya, Michelle; Kenny, Eimear E.; North, Kari E.; Launer, Lenore J.; Cade, Brian; Bis, Joshua C.; Cho, Michael; Lasky-Su, Jessica; Bowden, Donald W.; Cupples, L. Adrienne; Mak, Angel C. Y.; Becker, Lewis C.; Smith, Jennifer A.; Kelly, Tanika N.; Aslibekyan, Stella; Heckbert, Susan R.; Tiwari, Hemant K.; Yang, Ivana V.; Heit, John A.; Lubitz, Steven; Johnsen, Jill M.; Curran, Joanne E.; Wenzel, Sally E.; Weeks, Daniel E.; Rao, Dabeeru C.; Darbar, Dawood; Moon, Jee-Young; Tracy, Russell P.; Buth, Erin J.; Rafaels, Nicholas; Loos, Ruth J. F.; Durda, Peter; Liu, Yongmei; Hou, Lifang; Lee, Jiwon; Kachroo, Priyadarshini; Freedman, Barry I.; Levy, Daniel; Bielak, Lawrence F.; Hixson, James E.; Floyd, James S.; Whitsel, Eric A.; Ellinor, Patrick; Irvin, Marguerite R.; Fingerlin, Tasha E.; Raffield, Laura M.; Armasu, Sebastian M.; Wheeler, Marsha M.; Sabino, Ester C.; Blangero, John; Williams, L. Keoki; Levy, Bruce; Sheu, Wayne Huey-Herng; Roden, Dan M.; Boerwinkle, Eric; Manson, JoAnn; Mathias, Rasika A.; Desai, Pinkal; Taylor, Kent D.; Johnson, Andrew D.; Auer, Paul L.; Kooperberg, Charles; Laurie, Cathy C.; Blackwell, Thomas W.; Smith, Albert V.; Zhao, Hongyu; Lange, Ethan; Lange, Leslie; Rich, Stephen S.; Rotter, Jerome I.; Wilson, James G.; Scheet, Paul; Kitzman, Jacob O.; Lander, Eric; Engreitz, Jesse; Ebert, Benjamin; Reiner, Alexander P.; Jaiswal, Siddhartha; Abecasis, Gonçalo; Sankaran, Vijay; Kathiresan, Sekar; Natarajan, PradeepAge is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations leading to clonal expansion was associated with both hematologic cancer and coronary heart disease5, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP). Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer resulting in increased hematopoietic stem cell self-renewal. Overall, we observe that germline genetic variation shapes hematopoietic stem cell function leading to CHIP through mechanisms that are both specific to clonal hematopoiesis and shared mechanisms leading to somatic mutations across tissues.