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 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.
Additional work ongoing in my lab is focused on identifying genes involved in frailty/aging, with a particular focus on the role of mitochondria in longevity.
Lab Website: The Arking Lab
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Ashar FN, Mitchell RN, Albert CM, Newton-Cheh C, Brody JA, Muller-Nurasyid M, Moes A, Meitinger T, Mak A, Huikuri H, Junttila MJ, Goyette P, Pulit SL, Pazoki R, Tanck MW, Blom MT, Zhao X, Havulinna AS, Jabbari R, Glinge C, Tragante V, Escher SA, Chakravarti A, Ehret G, Coresh J, Li M, Prineas RJ, Franco OH, Kwok PY, Lumley T, Dumas F, McKnight B, Rotter JI, Lemaitre RN, Heckbert SR, O'Donnell CJ, Hwang SJ, Tardif JC, VanDenburgh M, Uitterlinden AG, Hofman A, Stricker BHC, de Bakker PIW, Franks PW, Jansson JH, Asselbergs FW, Halushka MK, Maleszewski JJ, Tfelt-Hansen J, Engstrom T, Salomaa V, Virmani R, Kolodgie F, Wilde AAM, Tan HL, Bezzina CR, Eijgelsheim M, Rioux JD, Jouven X, Kaab S, Psaty BM, Siscovick DS, Arking DE, Sotoodehnia N; SCD working group of the CHARGE Consortium. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. Eur Heart J. 2018 Aug 28. doi: 10.1093/eurheartj/ehy474. PMID:30169657. *Arking DE co-senior author.
van Setten J, Brody JA, Jamshidi Y, Swenson BR, Butler AM, Campbell H, Del Greco FM, Evans DS, Gibson Q, Gudbjartsson DF, Kerr KF, Krijthe BP, Lyytikainen LP, Muller C, Muller-Nurasyid M, Nolte IM, Padmanabhan S, Ritchie MD, Robino A, Smith AV, Steri M, Tanaka T, Teumer A, Trompet S, Ulivi S, Verweij N, Yin X, Arnar DO, Asselbergs FW, Bader JS, Barnard J, Bis J, Blankenberg S, Boerwinkle E, Bradford Y, Buckley BM, Chung MK, Crawford D, den Hoed M, Denny JC, Dominiczak AF, Ehret GB, Eijgelsheim M, Ellinor PT, Felix SB, Franco OH, Franke L, Harris TB, Holm H, Ilaria G, Iorio A, Kahonen M, Kolcic I, Kors JA, Lakatta EG, Launer LJ, Lin H, Lin HJ, Loos RJF, Lubitz SA, Macfarlane PW, Magnani JW, Leach IM, Meitinger T, Mitchell BD, Munzel T, Papanicolaou GJ, Peters A, Pfeufer A, Pramstaller PP, Raitakari OT, Rotter JI, Rudan I, Samani NJ, Schlessinger D, Silva Aldana CT, Sinner MF, Smith JD, Snieder H, Soliman EZ, Spector TD, Stott DJ, Strauch K, Tarasov KV, Thorsteinsdottir U, Uitterlinden AG, Van Wagoner DR, Volker U, Volzke H, Waldenberger M, Jan Westra H, Wild PS, Zeller T, Alonso A, Avery CL, Bandinelli S, Benjamin EJ, Cucca F, Dorr M, Ferrucci L, Gasparini P, Gudnason V, Hayward C, Heckbert SR, Hicks AA, Jukema JW, Kaab S, Lehtimaki T, Liu Y, Munroe PB, Parsa A, Polasek O, Psaty BM, Roden DM, Schnabel RB, Sinagra G, Stefansson K, Stricker BH, van der Harst P, van Duijn CM, Wilson JF, Gharib SA, de Bakker PIW, Isaacs A, Arking DE, Sotoodehnia N. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.Nat Commun. 2018 Jul 25;9(1):2904. doi: 10.1038/s41467-018-04766-9. PMID:30046033 *Arking DE co-senior author.
Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, Mychaleckyj JC, Taylor KD, Coresh J, Rotter JI, Bowerwinkle E, Pankratz N, Guallar E, Arking DE. Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. JAMA Cardiology. JAMA Cardiol. 2017 Oct 11. doi: 10.1001/jamacardio.2017.3683. PMID:29049454
Zhang Z, Guallar E, Ashar FN, Longchamps RJ, Castellani CA, Lane J, Grove ML, Coresh J, Sotoodehnia N, Ilkhanoff L, Boerwinkle E, Pankratz N, Arking DE. Association between Mitochondrial DNA Copy Number and Sudden Cardiac Death: Findings from the Atherosclerosis Risk in Communities Study (ARIC). Eur Heart J. 2017 Dec 7;38(46):3443-3448. PMID:29020391
The Autism Spectrum Disorders Working Group of the Psychiatric GWAS Consortium*. Meta-analysis of GWAS of over 16,000 individuals with Autism Spectrum Disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism. 2017. May 22;8:21. PMID:28540026. *Arking DE co-senior author.