Lack of success of Genome-Wide Association research

In the News Focus story “Major Heart Disease Genes Prove Elusive” (4 June, p. 1120), cardiovascular researcher D. Srivastava claims that Genome-Wide Association research “wasn’t worth the expenditure—but that was hard to say prospectively.”  The prospective optimism derived in part from the conventional interpretation that a high heritability value for a trait, such as incidence of heart disease, indicates a strong genetic contribution, which makes the trait “a potentially worthwhile candidate for molecular research” that might identify the specific genetic factors involved.[1] That interpretation warrants rethinking.[2] Heritability values are derived from analysis of data from relatives, e.g., the similarity of pairs of monozygotic twins (which share all their genes) can be compared with the similarity of pairs of dizygotic twins (which do not share all their genes).  The more that the former quantity exceeds the latter, the higher is the trait’s heritability.  However, even if the similarity among twins or a set of close relatives were associated with similarity of yet-to-be-identified genetic factors, the factors may not be the same from one set of relatives to the next, or from one environment to the next.  It could be that pairs of alleles, say, AAbbcbDDee, subject to a sequence of environmental factors, say, FghiJ, are associated, all other things being equal, with the same outcomes as alleles aabbCCDDEE subject to a sequence of environmental factors FgHiJ. The possibility that the underlying genetic and environmental factors influencing development of a trait may be heterogeneous puts an exclamation point on the consensus that most medically significant traits are associated with many genes of quite small effect.[3]

[1] Nuffield Council on Bioethics, chapter 11, (2002).

[2] P. J. Taylor, Biology & Philosophy 25, 1 (2010).

[3] M. I. McCarthy et al., Nature Reviews Genetics 9, 356 (2008).

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