Dan Arking, PhD

Associate Professor McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology Johns Hopkins University School of Medicine
Contact | Education | Interests | Research | Leadership | Publications | Sudden Cardiac Death

Education:

B.S.     University of Maryland, College Park, 1995
Ph.D.   Johns Hopkins University School of Medicine, 2001

Main Interests:

My research focuses on genomics of complex human disease, with the primary goal of identifying and characterizing genetics variants that modify risk for human disease.  Traditional approaches to identify genes involved in complex disease have relied upon screening candidate genes or family-based linkage studies in families with rare monogenic forms of disease.  Given the limited success of these approaches to identify genes contributing to common disease, our group has pioneered the use of genome-wide association studies (GWAS), which allow for an unbiased screen of virtually all common genetic variants in the genome.  We are currently developing improved GWAS methodology, as well as exploring the integration of additional genome level data (RNA expression, DNA methylation, protein expression) to improve the power to identify genetic influences of disease.  My lab is actively involved in researching autism, a childhood neuropsychiatric disorder, as well as cardiovascular genomics, with a focus on sudden cardiac death (SCD).  

Autism is a devastating neuropsychiatric condition with unknown pathophysiology. Autism spectrum disorders (ASD) have an estimated incidence of 1/200 and thus are more common than many other childhood disorders. Although ASD have a multifactorial etiology, it has a large genetic component, and it is becoming clear that comprehensive efforts involving large sample sizes and methods to reduce heterogeneity are necessary. Our group has recently demonstrated that common sequence changes in the CNTNAP2 and SEMA5A genes are associated with altered risk for ASD.  For both these genes, we have been able to demonstrate that gene expression is altered in brains obtained from autism patients relative to age- and sex-matched controls.  To identify additional genetic variants, we are performing a comprehensive and integrative screen of autism brains and matched controls, including genetic variation, methylation profiling, and gene expression. 

SCD is one of the leading causes of death in the United States, with ~462,000 of the 2,400,000 (19.3%) US deaths in 1999 classified as SCDs. From the standpoint of preventive care, SCD poses a huge burden since less than 10% of SCD victims survive, and approximately 2/3 of SCD victims do not have clinical symptoms that would warrant preventive intervention.  Thus, the use of genetics to identify individuals who are at high risk for SCD is crucial.  As a further complication, limited DNA resources are available for individuals who experience SCD due to the low survival rate.  We are working to expand the number of available SCD cases, and in addition are collecting hearts from SCD victims for gene expression, DNA methylation, and protein expression profiling.  In addition to directly identifying genes for SCD, we are examining intermediate quantitative traits, such as the QT interval, a measure of cardiac repolarization associated with SCD, as well as other ECG parameters.  Elucidating the genetic basis of electrical activity in the heart is likely to be a critical component to understanding SCD risk.   

For more information about causes, prevention, and research related to SCD risk, please visit the Sudden Cardiac Death Initiative website: pathology.jhu.edu/scd/index.html

Additional work ongoing in my lab is focused on identifying genes involved vascular calcification, frailty/aging, and Parkinson’s disease.  

Research Interests:       

• Genetics of complex disease
• Cardiovascular disease and sudden cardiac death
• Autism
• Development and implementation of novel GWAS analytical tools

Recognition and Leadership Roles:

• Member, The American Society for Human Genetics
• Scientific Advisory Board Member, Association for Eradication of Heart Attack (AEHA)
• Member, Simons Foundation Autism Research Initiative Review Board
• Member, Simons Foundation Autism Research Gene Advisory Board

Selected Publications:

Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC.  Association of human aging with a functional variant of klotho.  Proc Natl Acad Sci USA. 2002; 99(2):856-861.

Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, Becker LC, Dietz HC.  KLOTHO allele status and the risk for early-onset occult coronary artery disease.  Am. J. Hum. Genet. 2003; 72:1154-1161.

Arking DE, Chugh SS, Chakravarti A, Spooner PM.  Genomics in Sudden Cardiac Death.  Circ Res. 2004; 94:712-723.

Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC.  Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity.  Circ Res. 2005; 96(4):412-418.

Maitra A*, Arking DE*, Shivapurkar N, Ikeda M, Stastny V, Kassauei K, Sui G, Cutler DJ, Liu Y, Brimble SN, Noaksson K, Hyllner J, Schulz TC, Zeng X, Freed WJ, Crook J, Abraham S, Colman A, Sartipy P, Matsui S, Carpenter M, Gazdar AF, Rao M, Chakravarti A.  Genomic Alterations in Cultured Human Embryonic Stem Cells. Nat Genet. 2005; 37(10):1099-103.  *These authors contributed equally to the work.

Arking DE*, Pfeufer A*, Post W, Kao WH, Newton-Cheh C, Ikeda M, West K, Kashuk C, Akyol M, Perz S, Jalilzadeh S, Illig T, Gieger C, Guo CY, Larson MG, Wichmann HE, Marbán E, O'Donnell CJ, Hirschhorn JN, Kääb S, Spooner PM, Meitinger T, Chakravarti A.  A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.  Nat Genet. 2006; 38(6):644-651. *These authors contributed equally to the work.

Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH, Chakravarti A.  A common genetic variant in the neurexin-superfamily member CNTNAP2 increases familial risk of autism.  Am J Hum Genet. 2008; 82(1): 160-4.

Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ; Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism.  N Engl J Med. 2008;  358(7):667-75.

Kao WH*, Arking DE*, Post W*, Rea TD, Sotoodehnia N, Prineas RJ, Bishe B, Doan BQ, Boerwinkle E, Psaty BM, Tomaselli GF, Coresh J, Siscovick DS, Marbán E, Spooner PM, Burke GL, Chakravarti A.  Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations.  "Circulation. 2009; 119(7):940-51.  *These authors contributed equally to the work.

Arking DE, Khera A, Xing C, Kao WH, Post W, Boerwinkle E, Chakravarti A. Multiple Independent Genetic Factors at NOS1AP Modulate the QT Interval in a Multi-Ethnic Population.  "PLoS ONE. 2009; 4(1):e4333.

Pfeufer A*, Sanna S*, Arking DE*, Müller M, Gateva V, Fuchsberger C, Ehret GB, Orrú M, Pattaro C, Köttgen A, Perz S, Usala G, Barbalic M, Li M, Pütz B, Scuteri A, Prineas RJ, Sinner MF, Gieger C, Najjar SS, Kao WH, Mühleisen TW, Dei M, Happle C, Möhlenkamp S, Crisponi L, Erbel R, Jöckel KH, Naitza S, Steinbeck G, Marroni F, Hicks AA, Lakatta E, Müller-Myhsok B, Pramstaller PP, Wichmann HE, Schlessinger D, Boerwinkle E, Meitinger T, Uda M, Coresh J, Kääb S, Abecasis GR, Chakravarti A.  Common variants at ten loci modulate the QT interval duration in the QTSCD study.  "Nat Genet. 2009; 41(4):407-14. *These authors contributed equally to the work.

SanGiovanni JP*, Arking DE*, Iyengar SK, Elashoff M, Clemons TE, Reed GF, Henning AK, Sivakumaran TA, Xu X, DeWan A, Agrón E, Rochtchina E, Sue CM, Wang JJ, Mitchell P, Hoh J, Francis PJ, Klein ML, Chew EY, Chakravarti A. Mitochondrial DNA Variants of Respiratory Complex 1 that Uniquely Characterize Haplogroup T2 are Associated with Increased Risk of Age-Related Macular Degeneration. PLoS ONE. 2009; 4(5):e5508.  *These authors contributed equally to the work.

Arking DE, Chakravarti A.  Understanding cardiovascular disease through the lens of genome-wide association studies. Trends Genet. 2009; 25(9):387-94.

Benjamin EJ*, Rice KM*, Arking DE*, Pfeufer A*, van Noord C*, Smith AV*, Schnabel RB, Bis JC, Boerwinkle E, Sinner MF, Dehghan A, Lubitz SA, D'Agostino RB Sr, Lumley T, Ehret GB, Heeringa J, Aspelund T, Newton-Cheh C, Larson MG, Marciante KD, Soliman EZ, Rivadeneira F, Wang TJ, Eiríksdottir G, Levy D, Psaty BM, Li M, Chamberlain AM, Hofman A, Vasan RS, Harris TB, Rotter JI, Kao WH, Agarwal SK, Stricker BH, Wang K, Launer LJ, Smith NL, Chakravarti A, Uitterlinden AG, Wolf PA, Sotoodehnia N, Köttgen A, van Duijn CM, Meitinger T, Mueller M, Perz S, Steinbeck G, Wichmann HE, Lunetta KL, Heckbert SR, Gudnason V, Alonso A, Kääb S, Ellinor PT, Witteman JC. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.  "Nat Genet. 2009; 41(8):879-81 . *These authors contributed equally to the work.

Weiss LA*, Arking DE*; Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A.  A genome-wide linkage and association scan reveals novel loci for autism.  Nature 2009 Oct 8; 461(7265):802-8.  *These authors contributed equally to the work.

Pfeufer A*, van Noord C*, Marciante KD*, Arking DE*, Larson MG*, Smith AV*, Tarasov KV*, Müller M, Sotoodehnia N, Sinner MF, Verwoert GC, Li M, Kao WH, Köttgen A, Coresh J, Bis JC, Psaty BM, Rice K, Rotter JI, Rivadeneira F, Hofman A, Kors JA, Stricker BH, Uitterlinden AG, van Duijn CM, Beckmann BM, Sauter W, Gieger C, Lubitz SA, Newton-Cheh C, Wang TJ, Magnani JW, Schnabel RB, Chung MK, Barnard J, Smith JD, Van Wagoner DR, Vasan RS, Aspelund T, Eiriksdottir G, Harris TB, Launer LJ, Najjar SS, Lakatta E, Schlessinger D, Uda M, Abecasis GR, Müller-Myhsok B, Ehret GB, Boerwinkle E, Chakravarti A, Soliman EZ, Lunetta KL, Perz S, Wichmann HE, Meitinger T, Levy D, Gudnason V*, Ellinor PT*, Sanna S*, Kääb S*, Witteman JC*, Alonso A*, Benjamin EJ*, Heckbert SR*.  Genome-wide association study of PR interval. Nat Genet 2010; 42(2):153-9. *These authors contributed equally to the work.

Ellinor PT*, Lunetta KL*, Glazer NL*, Pfeufer A*, Alonso A*, Chung MK*, Sinner MF*, de Bakker PI, Mueller M, Lubitz SA, Fox E, Darbar D, Smith NL, Smith JD, Schnabel RB, Soliman EZ, Rice KM, Van Wagoner DR, Beckmann BM, van Noord C, Wang K, Ehret GB, Rotter JI, Hazen SL, Steinbeck G, Smith AV, Launer LJ, Harris TB, Makino S, Nelis M, Milan DJ, Perz S, Esko T, Köttgen A, Moebus S, Newton-Cheh C, Li M, Möhlenkamp S, Wang TJ, Kao WH, Vasan RS, Nöthen MM, MacRae CA, Stricker BH, Hofman A, Uitterlinden AG, Levy D, Boerwinkle E, Metspalu A, Topol EJ, Chakravarti A, Gudnason V, Psaty BM, Roden DM, Meitinger T, Wichmann HE, Witteman JC*, Barnard J*, Arking DE*, Benjamin EJ*, Heckbert SR*, Kääb S*.  Common variants in KCNN3 are associated with lone atrial fibrillation.  Nat Genet . 2010 Mar;42(3):240-4. *These authors contributed equally to the work.

Arking DE*, Reinier K*, Post W, Jui J, Hilton G, O’Connor A, Prineas RJ, Boerwinkle E, Psaty BM, Tomaselli GF, Rea T, Sotoodehnia N, Siscovick DS, Burke GL, Marban E, Spooner PM, Chakravarti A, Chugh SS.  Genome-Wide Association Study Identified GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest. PLoS One 2010 Mar 25; 5(3):e9879. *These authors contributed equally to the work.

Book Chapters:

Kane L, Priori SG, Napolitano C, Arking DE, Van Eyk J.  Genetics, genomics, and proteomics in sudden death and resuscitation.  In Cardiac Arrest, The Science and Practice of Resuscitation Medicine.  2^nd Edition.  Eds. N.A. Paradis, H.R. Halperin, K.B. Kern, V. Wenzel, & D.A. Chamberlain.  New York: Cambridge University Press, 2007.  70-89.

Arking DE. Genomics and Cardiovascular Disease.  In Genomics and Clinical Medicine.  Ed. D. Kumar. New York: Oxford University Press, 2008.  161-78.

Contact:

Dan E. Arking, Ph.D.

McKusick-Nathans Institute of Genetic Medicine
Johns Hopkins University School of Medicine
Broadway Research Building, Room 453
733 N. Broadway St.
Baltimore, MD 21205
(410) 502-4867
(410) 614-8600 (FAX)
E-mail: arking@jhmi.edu