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Genetic associations: false or true?

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Abstract

Genetic association studies for multigenetic diseases are like fishing for the truth in a sea of trillions of candidate analyses. Red herrings are unavoidably common, and bias might cause serious misconceptions. However, a sizeable proportion of identified genetic associations are probably true. Meta-analysis, a rigorous, comprehensive, quantitative synthesis of all the available data, might help us to separate the true from the false.

Section snippets

Empirical evidence, bias and heterogeneity

Lohmueller et al. have recently shown that these problems are not just theory [6]. In a large-scale empirical evaluation of 25 postulated genetic associations, they showed that the results of the first statistically significant (‘positive’) study were inflated when compared with the results of other published research on the same question. This is consistent with prior large-scale observations [7]. Omitting the first ‘positive’ study, is there still an association when only the remaining

A big picture of small effects

It is likely that most genuine genetic associations represent modest effects with odds ratios of 1.1–1.5 (i.e. a 10–50% relative increase in the likelihood of getting a disease). Any one polymorphism usually explains only 1–8% of the overall disease risk in the population. This might sound quite small, but the additive effect of several such risk factors could make up the 20–70% of the overall disease risk that is attributed to genetic factors in most common diseases. An adequately powered

Acknowledgements

J.P.A.I is also an Adjunct Professor of Medicine at the Division of Clinical Care Research, Department of Medicine, Tufts–New England Medical Center, Boston, MA, USA.

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