Genetics of type 2 diabetes-pitfalls and possibilities

Abstract

Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors. While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge. However, recent years have seen an explosion of genetic variants in risk and protection of T2D due to the technical development that has allowed genome-wide association studies and next-generation sequencing. Today, more than 120 variants have been convincingly replicated for association with T2D and many more with diabetes-related traits. Still, these variants only explain a small proportion of the total heritability of T2D. In this review, we address the possibilities to elucidate the genetic landscape of T2D as well as discuss pitfalls with current strategies to identify the elusive unknown heritability including the possibility that our definition of diabetes and its subgroups is imprecise and thereby makes the identification of genetic causes difficult.

Figure 1

The spectrum of diabetes subgroups. The data is from the ANDIS project (All New Diabetics in Scania) (http://andis.ludc.med.lu.se) in April 2012 which at that time included 5,800 newly diagnosed diabetic patients aged 0–100 years. The criteria used for diagnosis are as follows: T1D: age at onset <35 years, C-peptide < 0.2nmol/L and GAD antibodies >20; T1D with relative insulin deficiency if C-peptide 0.2–0.6 nmol/L. T2D: age at onset >35 years, C-peptide > 0.6 nmol/L, GAD antibodies <10; T2D with relative insulin deficiency C-peptide 0.2–0.6 nmol/L. LADA (latent autoimmune diabetes in adults): age at onset > 5 years, GAD antibodies >20; LADA light if GAD antibodies 10–20. The data clearly illustrates the difficulty classifying diabetic patients at diagnosis with 19% unclassifiable.

Figure 2

T2D risk variants. X axis shows the chromosomal location, Y shows the effect sizes and Z axis shows the year of discovery. Only 1 risk variant was reported in 1998; there were 2 in 2002, and today, we have a total of ~153 T2D variants.

Figure 3

T2D and glycemic trait associated variants. The variants are represented by gene names here, which could indicate that the location is present either in the gene, or in the vicinity of the gene. The black circle represents T2D, and the gene names in black in this represent variants only associated with T2D. The overlapping circles indicate additional reporting associations for that variant for instance, TCF7L2, KCNQ1, MTNR1B etc., are associated with T2D and also with beta-cell dysfunction. An ADCY5 variant is associated with 2 h insulin adjusted for 2 h glucose; 2 h glucose/T2D (in brown) *** variants in TMEM163 are also associated with fasting insulin, TCF7L2—associated with fasting and 2 h glucose and MADD variants associated with fasting proinsulin, fasting glucose and HOMA-B.