Genetic Liability of Type 1 Diabetes and the Onset Age Among 22,650 Young Finnish Twin Pairs

Abstract

Finland has the world's highest incidence of type 1 diabetes, and it is steadily increasing. We determined concordance rates and estimated heritability for type 1 diabetes in the Finnish Twin Cohort, a population-based twin cohort of 22,650 twin pairs. In addition, we studied age of onset in the first affected twin and discordance time between concordant twin pairs. Finnish twins born between 1958 and 1986 were followed for type 1 diabetes until 1998. We identified 228 twin pairs with type 1 diabetes: 44 monozygotic (MZ), 183 dizygotic (DZ), and 1 pair with unknown zygosity. The pairwise concordance for type 1 diabetes was 27.3% (95% CI 22.8 -31.8) in MZ and 3.8% (2.7-4.9) in DZ twins. The probandwise concordance was 42.9% (26.7-59.2) and 7.4% (2.2-12.6), respectively. The longest discordance times were 6.9 years among concordant MZ twins and 23.6 years among DZ twins. The risk for type 1 diabetes was highest in cotwins of the index twins diagnosed at a very young age. The model with additive genetic and individual environmental effects was the best-fitting liability model, with 88% of phenotypic variance due to genetic factors and the remaining variance due to unshared environmental factors. In conclusion, these nationwide twin data demonstrated high genetic liability for type 1 diabetes. Early-onset diabetes increases the risk in cotwins. However, the majority of affected MZ twin pairs remain discordant for type 1 diabetes. Diabetes 52: 1052-1055, 2003A recent study showed that Finland's record type 1 diabetes incidence increased predominantly in younger age-groups (1,2). The exact mechanism underlying the process leading to type 1 diabetes remains elusive, despite years of research. It is known that genes in the HLA region substantially influence the risk of type 1 diabetes and familial clustering (3,4). Several environmental factors have been proposed to contribute to its pathogenesis, but their causative role has not been established (5-7).Twins provide a powerful tool to investigate relative importance of genetic and environmental factors on traits by comparing of concordance in monozygotic (MZ) and dizygotic (DZ) twins. Finland is one of the few countries with a population-based twin cohort (8) offering uniquely large, representative, and therefore unbiased data on type 1 diabetes among twins. The objective of this study was to determine concordance rates and to estimate heritability for type 1 diabetes in the Finnish population-based cohort. Furthermore, we examined risk for progression to diabetes in cotwins in relation to age at onset of the first affected twin (index twin) and the discordance time among concordant twin pairs.Of 303 diabetic twins identified from different sources, 247 cases (in 228 pairs) had type 1 diabetes (116 females, 131 males), 28 had type 2 diabetes, 15 had secondary diabetes, and 13 had gestational diabetes. Of the type 1 diabetic twin pairs, 44 belonged to MZ pairs, 90 to opposite-sex DZ pairs, 93 to same-sex DZ pairs, and 1 to a same-sex pair of unknown zygosity, totaling 22...

Familial association between type 1 diabetes and other autoimmune and related diseases

“…The disease is thought to be triggered in susceptible individuals by environmental, demographic and ethnic factors, including parental country of origin, and by physiological factors and medical conditions such as enteroviral infections, old parental age at birth, preeclampsia, cesarean section delivery, increased birthweight, early exposure to cows' milk and high rate of postnatal growth [1][2][3]. Family history is an important risk factor shown in twins and singleton siblings [4][5][6]. The sibling relative risk is cited to be 15 but it depends critically on the age of onset and probably on the background incidence of the disease [7][8][9][10].…”

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

“…T1D has a high concordance in monozygotic (MZ) twins and intermediate concordance in dizygotic (DZ) twins (27% and 3.8% respectively) [5]. This is associated with a lifetime risk for the twin of an affected proband of 44% and 19% respectively [6].…”

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

“…Below we describe results for a few well-studied traits, each with GWASs with .10,000 samples and genome-wide imputation (.2 million SNPs), representing a range of complex trait genetic architectures (at least in terms of common variants): T1D, involving early-onset autoimmune destruction of the insulin-producing b-cells of the pancreas, has a population prevalence of roughly 0.5% and estimated heritability of 88% (Hyttinen et al 2003). GWAS of over 34,000 samples (Barrett et al 2009a,b;Hakonarson et al 2007Hakonarson et al , 2008Cooper et al 2008) have brought the list of validated T1D-risk associated loci to more than 40, explaining 80% of genetic variation of T1D [50% of which comes from the major histocompatability complex (MHC) region; Wei et al 2009].…”