Common (complex) traits

Most people, have come across complex traits such as heart rate, eye colour and height. But they also include common human diseases such as hypertension (high blood pressure), diabetes, and coronary heart disease.

We analyse available genomic data in phenotyped human populations to identify genes associated with these traits and diseases. These studies have provided a greater understanding of the biology linking genotype and phenotype (the traits that we see and measure).

The exciting thing about these studies is the capability to screen for trait-associated genes in the general population at high-resolution, and in an unbiased manner to find regions or genes that we may never have thought to look at.

Using this information we can begin to create ‘polygenic risk scores,’ which allows stratification of a population into groups with very different trajectories of lifetime risk.

Importantly, these genetic association studies have reinforced known disease associations and also suggested additional ones that could reveal unrecognized biology which may ultimately guide new therapies.

CARDIOVASCULAR TRAITS

We work on multiple cardiovascular traits, in particular electrocardiographic traits. An electrocardiogram (ECG) is a test which measures the electrical activity of your heart to show whether or not it is working normally. An ECG records the heart's rhythm and activity on a moving strip of paper, or a line on a screen. Through international collaborations (as part of the CHARGE Consortium) we analyse large population datasets with ECG measures and genomic data, and have successfully uncovered many new gene regions that play a role in determining the hearts electrical function.

publications

van Setten J, Verweij N, Mbarek H, Niemeijer MN, Trompet S, Arking DE, Brody JA, Gandin I, Grarup N, Hall LM, Hemerich D, Lyytikäinen LP, Mei H, Müller-Nurasyid M, Prins BP, Robino A, Smith AV, Warren HR, Asselbergs FW, Boomsma DI, Caulfield MJ, Eijgelsheim M, Ford I, Hansen T, Harris TB, Heckbert SR, Hottenga JJ, Iorio A, Kors JA, Linneberg A, MacFarlane PW, Meitinger T, Nelson CP, Raitakari OT, Silva Aldana CT, Sinagra G, Sinner M, Soliman EZ, Stoll M, Uitterlinden A, van Duijn CM, Waldenberger M, Alonso A, Gasparini P, Gudnason V, Jamshidi Y, Kääb S, Kanters JK, Lehtimäki T, Munroe PB, Peters A, Samani NJ, Sotoodehnia N, Ulivi S, Wilson JG, de Geus EJC, Jukema JW, Stricker B, van der Harst P, de Bakker PIW, Isaacs A. Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits. Eur J Hum Genet. 2019 Jan 24.

Bastiaenen R, Nolte IM, Munroe PB, Riese H, Nelson C, O'Connor H, Gang Y, Warren HR, Cabrera C, Reinhard W, Hengstenberg C, Rijsdijk FV, Spector T, Snieder H, Samani NJ, Jamshidi Y*, Behr ER*. The narrow-sense and common single nucleotide polymorphism heritability of early repolarization. Int J Cardiol. 2018 Oct 4. pii: S0167-5273(17)38065-8.

Bram Prins, Timothy J Mead, Jennifer Brody, ...Nona Sotoodehnia, Suneel Apte, Pim van der Harst, Kari Stefansson, Patricia Munroe, Dan Arking, Cecilia Lo, Yalda Jamshidi. Exome-chip meta-analysis identifies novel loci, including ADAMTS6 associated with cardiac conduction. Genome Biol. 2018 Jul 17;19(1):87.

Jessica van Setten, Jennifer Brody, Yalda Jamshidi, ...Bruno Stricker, Pim van der Harst, Cornelia Duijn, James Wilson, Sina Gharib, Paul de Bakker, Aaron Isaacs, Dan Arking, and Nona Sotoodehnia. 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.

Honghuang Lin; Jessica van Setten; Albert V. Smith; ...Caroline Hayward; Marcus Dörr; Yalda Jamshidi; Folkert W. Asselbergs; Charles Kooperberg; Terho Lehtimäki; James G. Wilson; Patrick T. Ellinor; Steven A. Lubitz; Aaron Isaacs. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circ Genom Precis Med. 2018;May 11(5):e002037.

Nathan A. Bihlmeyer, Jennifer A. Brody, Albert Vernon Smith, Helen R. Warren, ...Mark Eijgelsheim, Marcus Dörr, Yalda Jamshidi, Folkert W. Asselbergs, Charles Kooperberg, Terho Lehtimäki, Dan E. Arking, Nona Sotoodehnia. ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. Circ Genom Precis Med. 2018;11:e001758.

Nolte IM, Jansweijer JA, Riese H, Asselbergs FW, van der Harst P, Spector TD, Pinto YM, Snieder H, Jamshidi Y. A Comparison of Heritability Estimates by Classical Twin Modeling and Based on Genome-Wide Genetic Relatedness for Cardiac Conduction Traits. Twin Res Hum Genet. 2017 Dec;20(6):489-498.

van den Berg ME, Warren HR, Cabrera CP, Verweij N, Mifsud B, Haessler J,....., Jamshidi Y, van Duijn CM, Zeggini E, Jukema JW, Asselbergs FW, Samani NJ, Lehtimäki T, Gudnason V, Wilson J, Lubitz SA, Kääb S, Sotoodehnia N, Caulfield MJ, Palmer CNA, Sanna S, Mook-Kanamori DO, Deloukas P, Pedersen O, Rotter JI, Dörr M, O'Donnell CJ, Hayward C, Arking DE, Kooperberg C, van der Harst P, Eijgelsheim M, Stricker BH, Munroe PB. Discovery of novel heart rate-associated loci using the Exome Chip. Hum Mol Genet. 2017 Jun 15;26(12):2346-2363.

Evans DS, Avery CL, Nalls MA, Li G, Barnard J, Smith EN, ....., Jamshidi Y, Kerr KF, Liu F, Liu Y, Lohman KK, Magnani JW, Maher JF, Mehra R, Meng YA, Musani SK, Newton-Cheh C, North KE, Psaty BM, Redline S, Rotter JI, Schnabel RB, Schork NJ, Shohet RV, Singleton AB, Smith JD, Soliman EZ, Srinivasan SR, Taylor HA Jr, Van Wagoner DR, Wilson JG, Young T, Zhang ZM, Zonderman AB, Evans MK, Ferrucci L, Murray SS, Tranah GJ, Whitsel EA, Reiner AP; CHARGE QRS Consortium, Sotoodehnia N. Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. Hum Mol Genet. 2016 Oct 1;25(19):4350-4368.

van der Harst P, van Setten J, Verweij N,......, Newton-Cheh C, Hicks AA, Chambers JC, Jamshidi Y*, Visel A*, Christoffels VM*, Isaacs A*, Samani NJ*, de Bakker PIW*. 52 Genetic Loci Influencing Myocardial Mass. J Am Coll Cardiol. 2016 Sep 27;68(13):1435-1448.

Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann TT, Sotoodehnia N,...., Gudnason V, Jamshidi Y, Salomaa V, Felix SB, Sanna S, Ritchie MD, Stricker BH, Stefansson K, Boyer LA, Cappola TP, Olsen JV, Lage K, Schwartz PJ, Kääb S, Chakravarti A, Ackerman MJ, Pfeufer A, de Bakker PI, Newton-Cheh C. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet. 2014 Aug;46(8):826-36.

Magnani JW, Brody JA, Prins BP, Arking DE,......, Boerwinkle E, Jamshidi Y, Sotoodehnia N; CHARGE Consortium; NHLBI Exome Sequencing Project (ESP); UK10K. Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Circ Cardiovasc Genet. 2014 Jun;7(3):365-73.

den Hoed M, Eijgelsheim M, Esko T, Brundel BJ, Peal DS, Evans DM, Nolte IM, Segrè AV, Holm H,....., Jamshidi Y,............, Visscher PM, Willer C, Franke L; Global BPgen Consortium; CARDIoGRAM Consortium, Erdmann J, Thompson JR; PR GWAS Consortium, Pfeufer A; QRS GWAS Consortium, Sotoodehnia N; QT-IGC Consortium, Newton-Cheh C; CHARGE-AF Consortium, Ellinor PT, Stricker BH, Metspalu A, Perola M, Beckmann JS, Smith GD, Stefansson K, Wareham NJ, Munroe PB, Sibon OC, Milan DJ, Snieder H, Samani NJ, Loos RJ. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat Genet. 2013 Jun;45(6):621-31.

Sotoodehnia N, Isaacs A, de Bakker PI, Dörr M, Newton-Cheh C, Nolte IM, van der Harst P,....., Jamshidi Y*, Stricker BH*, Samani NJ*, Kääb S*, Arking DE*. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet. 2010 Dec;42(12):1068-76.

Eijgelsheim M, Newton-Cheh C, Sotoodehnia N, de Bakker PI,......., Jamshidi Y, Uitterlinden AG, Folsom AR, Larson MG, Wilson JF, Penninx BW, Snieder H, Pramstaller PP, van Duijn CM, Lakatta EG, Felix SB, Gudnason V, Pfeufer A, Heckbert SR, Stricker BH, Boerwinkle E, O'Donnell CJ. Genome-wide association analysis identifies multiple loci related to resting heart rate. Hum Mol Genet. 2010 Oct 1;19(19):3885-94.

Jamshidi Y, Nolte IM, Spector TD, Snieder H. Novel genes for QTc interval. How much heritability is explained, and how much is left to find? Genome Med. 2010 May 27;2(5):35.

Nolte IM, Wallace C, Newhouse SJ, Waggott D, Fu J, Soranzo N, Gwilliam R, Deloukas P, Savelieva I, Zheng D, Dalageorgou C, Farrall M, Samani NJ, Connell J, Brown M, Dominiczak A, Lathrop M, Zeggini E, Wain LV; Wellcome Trust Case Control Consortium; DCCT/EDIC Research Group, Newton-Cheh C, Eijgelsheim M, Rice K, de Bakker PI; QTGEN consortium, Pfeufer A, Sanna S, Arking DE; QTSCD consortium, Asselbergs FW, Spector TD, Carter ND, Jeffery S, Tobin M, Caulfield M, Snieder H, Paterson AD, Munroe PB, Jamshidi Y. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PLoS One. 2009 Jul 9;4(7):e6138.

Dalageorgou C, Ge D, Jamshidi Y, Nolte IM, Riese H, Savelieva I, Carter ND, Spector TD, Snieder H. Heritability of QT interval: how much is explained by genes for resting heart rate? J Cardiovasc Electrophysiol. 2008 Apr;19(4):386-91.