Dr Ralph McGinnis

Relative power of association and linkage.

Relative power of association and linkage. [American Journal of Human Genetics, doi: 10.1016/S0002-9297(07)62965-6]


Dr Ralph McGinnis conducts collaborative and independent statistical genetics research aimed at identifying DNA variants that cause complex disease or alter therapeutic drug response and also pursues research aimed at characterising and understanding ethnic variation.

Ralph's career in Genetics began with postdoctoral work in the Department of Genetics, University of Pennsylvania (1990-1997). During his PhD (Psychobiology, Temple University) he performed neuroendocrine analysis of genetically obese [ob/ob] mice and became convinced that genetics - by systematically searching along each chromosome in order to discover disease-causing genes - offered the most promising approach to understanding disease etiology. He was also very attracted by the mathematical nature of this type of genetic research having obtained his first degree in Mathematics (BS, University of Delaware).

During his postdoctoral work in the Genetics laboratory of Richard Spielman, Ralph performed both wet lab and mathematical work and, in collaboration with Dr Spielman and Warren Ewens, introduced the Transmission/Disequilibrium test (TDT). Subsequently, he published general equations for comparing power to detect disease genes by "association" (TDT) or by "linkage" (ASP test), discovering that the derived equations subsume as special cases analogous equations of Risch and Merikangas.

The two "saddle-shaped" surfaces in the graph are from Ralph's work and compare the magnitudes of Pt and Ps, the two key probabilities that drive detection of disease genes by association or by linkage. Pt (association) is much greater than Ps (linkage) across the entire genetic parameter space - thus giving a visual generalisation of Risch and Merikangas' original "thought experiment", which first argued that genome-wide association studies (GWAS) could detect disease genes not detectable by linkage (see Science 273:1516-1517, 1996).

After employment in the United Kingdom as a statistical geneticist with the pharmaceutical company SmithKline Beecham where he led the company's Genetics of Schizophrenia programme, Ralph joined the Sanger Institute in late 2004 and has worked on a variety of disease association and pharmacogenetic projects. In collaboration with Panos Deloukas, he led statistical genetic analysis of GWAS projects which identified DNA variants associated with Celiac disease and with response to the anti-coagulant medication warfarin.

Chromosomal location of admixed DNA visualised by the RHH method.

Chromosomal location of admixed DNA visualised by the RHH method. [Human Molecular Genetics, doi: 10.1093/hmg/ddq102]


More recently, he has played lead roles in the HapMap3 project and in GWAS analysis of Pre-Eclampsia for the Wellcome Trust Case Control Consortium 3 (WTCCC3). He has also recently published a novel method (called "RHH") which uses GWAS data to visualise the genome mosaicism and chromosomal location(s) of DNA of different ancestry in admixed subjects descended from two different continental groups as illustrated in the figure at right. The red dashes adjacent to a chromosome indicate the location(s) of DNA from Subsahara Africa in admixed individuals whose ancestry is mainly European, the first subject being a WTCCC1 control and the second being HapMap European (CEU) subject NA12872. The RHH paper appears to be the first report of chromosomal locations of admixed, non-European DNA in HapMap European subjects.

Selected Publications

  • Integrating common and rare genetic variation in diverse human populations.

    International HapMap 3 Consortium, Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, Peltonen L, Dermitzakis E, Bonnen PE, Altshuler DM, Gibbs RA, de Bakker PI, Deloukas P, Gabriel SB, Gwilliam R, Hunt S, Inouye M, Jia X, Palotie A, Parkin M, Whittaker P, Yu F, Chang K, Hawes A, Lewis LR, Ren Y, Wheeler D, Gibbs RA, Muzny DM, Barnes C, Darvishi K, Hurles M, Korn JM, Kristiansson K, Lee C, McCarrol SA, Nemesh J, Dermitzakis E, Keinan A, Montgomery SB, Pollack S, Price AL, Soranzo N, Bonnen PE, Gibbs RA, Gonzaga-Jauregui C, Keinan A, Price AL, Yu F, Anttila V, Brodeur W, Daly MJ, Leslie S, McVean G, Moutsianas L, Nguyen H, Schaffner SF, Zhang Q, Ghori MJ, McGinnis R, McLaren W, Pollack S, Price AL, Schaffner SF, Takeuchi F, Grossman SR, Shlyakhter I, Hostetter EB, Sabeti PC, Adebamowo CA, Foster MW, Gordon DR, Licinio J, Manca MC, Marshall PA, Matsuda I, Ngare D, Wang VO, Reddy D, Rotimi CN, Royal CD, Sharp RR, Zeng C, Brooks LD and McEwen JE

    Nature 2010;467;7311;52-8

  • Visualizing chromosome mosaicism and detecting ethnic outliers by the method of "rare" heterozygotes and homozygotes (RHH).

    McGinnis RE, Deloukas P, McLaren WM and Inouye M

    Human molecular genetics 2010;19;13;2539-53

  • A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose.

    Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, Whittaker P, Ranganath V, Kumanduri V, McLaren W, Holm L, Lindh J, Rane A, Wadelius M and Deloukas P

    PLoS genetics 2009;5;3;e1000433

  • Newly identified genetic risk variants for celiac disease related to the immune response.

    Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D, Gwilliam R, Takeuchi F, McLaren WM, Holmes GK, Howdle PD, Walters JR, Sanders DS, Playford RJ, Trynka G, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, O'Morain C, Kennedy NP, Kelleher D, Pennington DJ, Strachan DP, McArdle WL, Mein CA, Wapenaar MC, Deloukas P, McGinnis R, McManus R, Wijmenga C and van Heel DA

    Nature genetics 2008;40;4;395-402

  • Treasure hunting in a new era: genotyping of single nucleotide polymorphisms and the search for complex disease genes by association scans.

    McGinnis R

    Psychiatric genetics 2002;12;2;63-6

  • Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland.

    McGinnis RE, Fox H, Yates P, Cameron LA, Barnes MR, Gray IC, Spurr NK, Hurko O and St Clair D

    Nature genetics 2001;28;2;128-9

  • General equations for Pt, Ps, and the power of the TDT and the affected-sib-pair test.

    McGinnis R

    American journal of human genetics 2000;67;5;1340-7

[Wellcome Library, London]

Statistical Genetics of Disease association, Drug response, and Ethnic Variation

Related links:

* quick link - http://q.sanger.ac.uk/effmumd3