1. ¹Department of Genetics and Development, Columbia University, New York, NY, USA
2. ²Department of Psychiatry, Columbia University, New York, NY, USA
3. ³Columbia Genome Center, Columbia University, New York, NY, USA
4. ⁴Division of Medical Genetics, New York State Psychiatric Institute, New York, NY, USA
5. ⁵Finnish Genome Center, University of Helsinki, Helsinki, Finland
6. ⁶Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland

Correspondence: Dr JD Terwilliger, 60 Haven Avenue, #15-C, New York, NY 10032, USA. Tel: +358 40 7467 277; E-mail: joseph.terwilliger@helsinki.fi

Received 16 July 2005; Revised 12 December 2005; Accepted 27 December 2005; Published online 15 February 2006.

Abstract

The International HapMap Project was proposed in order to quantify linkage disequilibrium (LD) relationships among human DNA polymorphisms in an assortment of populations, in order to facilitate the process of selecting a minimal set of markers that could capture most of the signal from the untyped markers in a genome-wide association study. The central dogma can be summarized by the argument that if a marker is in tight LD with a polymorphism that directly impacts disease risk, as measured by the metric r², then one would be able to detect an association between the marker and disease with sample size that was increased by a factor of 1/r² over that needed to detect the effect of the functional variant directly. This 'fundamental theorem' holds, however, only if one assumes that the LD between loci and the etiological effect of the functional variant are independent of each other, that they are statistically independent of all other etiological factors (in exposure and action), that sampling is prospective, and that the estimates of r² are accurate. None of these are standard operating assumptions, however. We describe the ramifications of these implicit assumptions, and provide simple examples in which the effects of a functional variant could be unequivocally detected if it were directly genotyped, even as markers in high LD with the functional variant would never show association with disease, even in infinite sample sizes. Both theoretical and empirical refutation of the central dogma of genome-wide association studies is thus presented.