The genetics of T2 is complicated. As of 2011 36 genes had been identified that were associated with T2 risk, but mostly they all were small contributors to the risk. It just seems that they can add up. That being said TCF7L2 is perhaps the greatest risk factor and raises the risk of T2 by 50% (that actually isn’t very strong). Here is what Williams (a classic endocrinology textbook says):
Type 2 diabetes provides a useful example of what GWAS have accomplished. Screening of large populations in which the prevalence of type 2 diabetes is high (approaching 10%) has uncovered 19 candidate genes to date. One of these genes, the transcription factor TCF7L2, is strongly associated with the existence and predictive development of insulin-deficient type 2 diabetes in multiple populations. Carriers of the TCF7L2 risk alleles have impaired glucose-stimulated insulin secretion and diminished augmentation of insulin secretion by incretin hormones such as GLP1 and gastric inhibitory polypeptide.
Note that GWAS is Genome Wide Association Study. Below is the full list of Type 2 genes in the book:
Williams further notes:
Transcription Factor 7-Like 2 Gene Grant and colleagues [1] genotyped 228 microsatellite markers in Icelandic patients with T2DM and in controls. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with T2DM. This was replicated in a Danish cohort and in a U.S. cohort. Compared with noncarriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high-mobility group box containing transcription factors previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway. In a follow-up study, Florez and colleagues [2] observed that specific polymorphisms in TCF7L2 increase the risk of progression from IGT to T2DM, and this effect is mediated through a reduction of glucose-induced insulin secretion.
68. Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38:320-323.
69. Florez JC, Jablonski KA, Bayley N, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006;355:241-250
Later in a general discussion of T2 diabetes genes it is noted:
1. A large number of genes are associated with increased susceptibility to this disease. The approximately 30 genes identified to date are thought to account for a small proportion (estimated at no more than 5% to 10%) of the total genetic risk for diabetes in the population.
2. The genes identified to date individually lead to a modest increase in the risk of diabetes. Persons with these individual polymorphisms have odds ratios between 1.10 and 1.45 when compared with individuals who do not have the at-risk polymorphisms.
3. The presence of multiple at-risk polymorphisms in a single individual substantially increases the risk of developing diabetes.
4. A significant proportion of the genetic variants associated with increased risk for diabetes appear to do so by inhibiting insulin secretion. Very few appear to increase insulin resistance or obesity. Whether this is a reflection of the relative importance of the roles of these factors in the pathogenesis of T2DM or whether the design of the GWAS did not allow genetic risk factors for insulin resistance and obesity to be identified is yet to be determined.
Hope that is helpful.