GWA - PROgRESS Genome-wide association studies provide new...

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15 25 35 45 55 65 30 40 50 60 20 10 5 0 10 15 % Body mass index Non-diabetic patients (mean age 59) Diabetic patients (mean age 64) Genome-wide association studies (GWAS) promised to greatly enhance our under- standing of the genetic basis of common and complex diseases. Companies such as Affymetrix and Illumina have developed chips that can capture information from more than two-thirds of the common vari- ation in the human genome. Approximately 300–500,000 SNPs can be analysed using these chips. Importantly, this can now be done for several thousands of DNA samples at costs that are within the scope of large project grants. This technology recently facilitated rapid progress in type 2 diabetes genetic research. This is all the more remarkable because type 2 diabetes does not have a strong genetic component compared with some other com- mon traits, and was previously described as ‘a geneticist’s nightmare’ 1,2 . Nevertheless, early results have been excellent, yielding six new replicating gene regions. Here I discuss the insights into type 2 diabetes genetics that have been provided by these new findings. I consider where diabe- tes genetic studies might go from here, and present a perspective that may be applicable to other common traits. I also briefly discuss the wider implications that surround the identification of a common gene that predis- poses to type 2 diabetes by altering fat mass. The geneticist’s nightmare Type 2 diabetes is one of the leading health problems throughout the developed world and is becoming increasingly important in the developing world. It has risen in preva- lence dramatically in the past two generations as we have come to lead increasingly sed- entary lifestyles and as food has become more plentiful. Obesity, defined as a body mass index (BMI) of greater than 30 kgm –2 increases the risk of type 2 diabetes. Such a strong environmental component to a dis- ease should perhaps have deterred geneticists from studying the disorder. However, there are many obese people who do not suffer from diabetes and many non-obese people who do, showing that obesity is not the only factor involved in the aetiology of type 2 diabetes (FIG. 1) . In the past 10 years, geneticists have devoted a large amount of effort to finding type 2 diabetes genes. These efforts have included many candidate-gene studies, exten- sive efforts to fine map linkage signals 3 , and an international linkage consortium that was perhaps the best example of a multi-centre collaboration in common-disease genetics. Of these efforts, only the candidate-gene studies produced unequivocal evidence for common variants involved in type 2 diabetes. These are the E23K variant in the potassium inwardly-rectifying channel, subfamily J, member 11 ( KCNJ11 ) gene 4–6 , the P12A variant in the peroxisome proliferator- activated receptor- γ ( PPARG ) gene 7 , and common variation in the transcription factor 2, hepatic ( TCF2 ) 8,9 and the Wolfram syndrome 1 ( WFS1
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This note was uploaded on 03/01/2010 for the course NPB 97952 taught by Professor ? during the Fall '09 term at UC Davis.

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GWA - PROgRESS Genome-wide association studies provide new...

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