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Response to 'Familial risks in understanding type 1 diabetes genetics'

Nature Reviews Genetics volume 13, page 146 (2012)Cite this article

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Relating to our Review article published in this journal (Understanding type 1 diabetes through genetics: advances and prospects. Nature Reviews Genetics 12, 781–792)1, we thank Kari Hemminki (Familial risks in understanding type 1 diabetes genetics. Nature Reviews Genetics 17 Jan 2012 (doi:10.1038/nrg3069-c1))2 for bringing up an important point. The value of the sibling relative risk (λs) is not an immutable constant but depends on the population and, in the same population, it may change over time as evolving environmental exposures alter trait heritability. Sweden and other Scandinavian countries offer a good example. There, the incidence of type 1 diabetes (T1D) is substantially higher than that in the United Kingdom3,4 and North America4,5, which are geographic regions that are the origin of most population samples used to estimate allele frequencies and odds ratios. Given the dramatic and variable T1D incidence increases in recent decades3,4, a large portion of these geographic differences can be assumed to be environmental. Consequently, high-incidence regions will be expected to show lower heritability.

A precise estimate of the 'missing heritability' requires solid documentation of incidence and familial relationships that can be assured only by population-based disease registries with pedigree information in the same region or regions from which the genotyped case–control samples originate. A second-best approach might be the use of hospital discharge records that are linked to family relationship databases, as done by Hemminki et al.6. That study found a λs of 12, suggesting that the widely quoted (and decades-old) value of 15 may be an overestimate. One limitation of that study, and a potential source of underestimate, was that it was constrained to T1D onset under the age of 20 and would have missed affected siblings that were discordant for age of onset. Approximately 20% of T1D cases are diagnosed after the age of 20 and, even in monozygotic twins, ages of onset can differ by many years7.

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References

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  1. Endocrine Genetics Laboratory, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

    Constantin Polychronakos & Quan Li

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  1. Constantin Polychronakos
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  2. Quan Li
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Correspondence to Constantin Polychronakos.

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Polychronakos, C., Li, Q. Response to 'Familial risks in understanding type 1 diabetes genetics'. Nat Rev Genet 13, 146 (2012). https://doi.org/10.1038/nrg3069-c2

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