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'Racial' differences in genetic effects for complex diseases

Abstract

'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond1,2. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases3,4,5,6 influenced by a large number of genes7. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.

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Figure 1: Frequencies of the allele(s) or genotype(s) of interest in control populations of various descents in each meta-analysis of gene-disease associations.
Figure 2: Odds ratios for the observed genetic association in studies of groups of various descents in each meta-analysis of gene-disease associations.
Figure 3: Correlation between the available total sample size and the I2 for the observed heterogeneity between the frequency estimates (a) and between the odds ratios (b) of the 'racial' groups in each meta-analysis.

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Acknowledgements

J.P.A.I. generated the idea for this project and wrote the protocol that was further elaborated by the other two authors. E.E.N. carried out additional data extraction with help from T.A.T. These two authors carried out the statistical analyses with contribution from J.P.A.I. All authors interpreted the data and the analyses. The final draft was written by J.P.A.I. and commented on critically by the other two authors. We thank D. Contopoulos-Ioannidis for her scientific contribution to important background work for this project and A. Wu, S. Glatt, M. Preisig, A. Lalovic, R. Inzelberg and L. Le Marchand for providing additional data on their published meta-analyses. The project was supported by a PENED grant from the General Secretariat for Research and Technology, Greece and the European Commission.

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Correspondence to John P A Ioannidis.

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Supplementary information

Supplementary Fig. 1

Control frequencies and effect sizes for overall-validated marker-disease associations. (PDF 46 kb)

Supplementary Table 1

Included and excluded meta-analyses of gene-diseases associations. (PDF 23 kb)

Supplementary Table 2

Within-race and between-race variance for control frequencies. (PDF 3 kb)

Supplementary Table 3

Pair-wise comparisons for control frequencies. (PDF 5 kb)

Supplementary Table 4

Within-race and between-race variance for odds ratios. (PDF 5 kb)

Supplementary Table 5

Pair-wise comparisons for odds ratios. (PDF 4 kb)

Supplementary Note (PDF 121 kb)

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Ioannidis, J., Ntzani, E. & Trikalinos, T. 'Racial' differences in genetic effects for complex diseases. Nat Genet 36, 1312–1318 (2004). https://doi.org/10.1038/ng1474

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