Heritability of type 1 diabetes and type 2 diabetes
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page159-160
2025-11-03
63
Heritability is a measure of the genetic influence on a particular trait. For type 1 diabetes, the risk in offspring of an affected mother is 2–4%, whereas the risk from an affected father is as high as 5–8%. The sibling relative risk (RR) of type 1 diabetes is estimated at 15. Type 1 diabetes concordance in monozygotic twins is ~40%, but is dependent on age of diagnosis. In twins with type 1 diabetes, the age at diagnosis was strongly correlated in identical pairs (RR = 0.94) compared to non- identical twins (RR = 0.59). Type 1 diabetes results from the interplay between genetic, epigenetic, and environmental factors. Genetic studies have reported >200 loci associated with type 1 diabetes, which explain ~80% of the heritability. Environmental factors incorporate enterovirus infections, including viruses of the picorna family, as they are seen more often among individuals with newly diagnosed type 1 diabetes than in the general population, and they precede the appearance of autoantibodies, environmental pollutants, gut flora variations, and vitamin D exposure.
Type 2 diabetes clusters in families and the risk of developing type 2 diabetes depend on both genetic and environmental factors. Heritability parameters facilitate understanding of the genetic architecture of complex traits such as type 2 diabetes. However, heritability estimates have varied between 25% and 80% in different studies; the highest estimates are seen in those studies with the longest follow- up periods. The lifetime risk of developing type 2 diabetes is 40% for individuals who have one parent with type 2 diabetes and almost 70% if both parents are affected. The concordance rate of type 2 diabetes in monozygotic twins is ~70%, while the concordance in dizygotic twins is only 20–30%. The proband- wise concordance rates (number of affected twins having a co- twin with diabetes) for monozygotic twins vary between 34% and 100%. The relative risk for first- degree relatives – that is, the risk of developing type 2 diabetes if you have an affected parent or sibling compared to the general population – is ~3 and ~6 if both parents are affected. However, these figures vary depending on the cohort and population studied.
The prevalence of type 2 diabetes varies widely among populations, from a few percent among White Europeans to as high as 50% among the Pima in Arizona [46]. While part of the observed ethnic variability could be attributed to environmental and cultural factors, some of the variation seems to depend on genetic differences.
Despite these reservations, there is no doubt the risk of type 2 diabetes is partly determined by genetic factors, many of which have already been identified, and while each identified variant explains only a very small proportion of the risk of type 2 diabetes in humans, overall they have contributed to our understanding of disease pathogenesis. One should also keep in mind that the variance explained by a risk allele in a population is not necessarily an indicator of its importance in specific individuals, nor is it proportional to the affected pathway’s importance or potential as a therapeutic target.
The more than 1000 SNPs identified explain less than 20% of the heritability of type 2 diabetes. There are many possible explanations for the missing heritability, including assumptions made about the genetic architecture of the disease and the definitions of heritability. The estimations of heritability explained assume that only additive effects determine disease risk and that the risk follows the liability threshold model; that is, that the genetic and environmental effects combine to form a normal distribution of liability and that disease arises in individuals surpassing a certain threshold in the distribution. If these assumptions are not true, the estimate of heritability explained will not be correct.
Intrauterine effects can also affect heritability estimates because monozygotic twins are often monochorionic, which results in growth retardation compared to dizygotic twins, and low birth weight is associated with increased risk of type 2 diabetes later in life. Furthermore, there could be other explanations for the missing heritability problem. Heritability can only be estimated from the most recent generations for which information on affected status is available, whereas most of the variants studied thus far are ancestral variants hundreds of generations old. We do not know whether these ancestral variants (which have modest effects and have escaped purifying selection) can really explain the diabetes epidemic we see in the most recent generations or whether this can be ascribed to rare variants with stronger effects.
Moreover, heritability estimates are based on the top single- nucleotide polymorphisms (SNPs) from genome- wide association studies (GWAS); novel methods have been proposed that consider (i) a 0–1 scale as opposed to liability; (ii) ascertainment bias; and (iii) quality control of the GWAS SNPs. Estimating the proportion of variance explained by all SNPs in GWAS as opposed to only the most significantly associated SNPs could result in a more detailed estimate of heritability [48]. Applying an approach that considers all SNPs on the chip could in fact explain a much larger proportion of the narrow- sense heritability (>50%), supporting the existence of numerous yet unidentified loci with smaller effects.
الاكثر قراءة في الوراثة
اخر الاخبار
اخبار العتبة العباسية المقدسة
