As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene
IL2RA (
CD25), which encodes a subunit (IL-2Rα) of ...the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (
P
=
6.5×
10
−8) for a T1D locus in the
CD25 region of chromosome 10p15 and replicated the association in the family collection (
P
=
7.3×
10
−3; combined
P
=
1.3×
10
−10). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.
Recent research using the Avon Longitudinal Study of Parents and Children (ALSPAC) demonstrated an association between maternal grandmother smoking in pregnancy and the autistic traits of impaired ...social communication and repetitive behaviour in granddaughters but not grandsons, but of paternal grandmother smoking and early development of myopia in the grandchild. Here we investigate whether grandmaternal smoking in pregnancy is associated with intolerance to loud sounds. ALSPAC collected information during the index pregnancy from the study parents on the smoking habits, social and other features of their own parents. Maternal report when the child was aged 6 and 13 included hating loud sounds; at age 11 the child was tested for volume preference for listening to music through headphones. Statistical analysis compared results for grandchildren in relation to whether a parent had been exposed in utero to maternal smoking, adjusted for their grandparents' social and demographic attributes. We hypothesised that there would be sex differences in the effects of grandmaternal prenatal smoking, based on previous intergenerational studies. For 6-year-old children maternal report of intolerance to loud noise was more likely in grandsons if the maternal grandmother had smoked adjusted odds ratio (AOR) 1.27; 95% confidence interval (CI) 1.03,1.56; P = 0.025, but less likely in girls AOR 0.82; 95%CI 0.63,1.07 Pinteraction <0.05. If the paternal grandmother had smoked the grandchildren were less likely to be intolerant, especially girls. The objective measure of choice of volume for music through headphones showed that grandsons of both maternal and paternal smoking grandmothers were less likely to choose high volumes compared with granddaughters (P<0.05). In line with our prior hypothesis of sex differences, we showed that grandsons were more intolerant of loud sounds than granddaughters particularly at age 6, and this was confirmed by objective measures at age 11.
Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural ...history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10−8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10−11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10−27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the “eczema plus early wheeze” and “eczema plus asthma” phenotypes.
There are animal data that indicate that prenatal environmental exposures have sex-specific effects on subsequent generations. In humans, an increase in birthweight has been reported if the maternal ...grandmother had smoked in the pregnancy giving rise to the mother. Here we assess whether prenatal exposure of either parent to cigarette smoke has a sex-specific effect on the grandchild's birth measurements.
Information from 12707 maternal and 9677 paternal grandmothers of children in the Avon Longitudinal Study of Parents and Children (ALSPAC) concerned whether they had smoked while expecting the study parent. Study children were weighed and measured at birth. Analyses to test effects of grandmaternal prenatal smoking used multiple regression allowing for several potential confounders; analyses were restricted to births to non-smoking study mothers.
After adjustment, the average birthweight, birth length and bmi measurements of the grandsons (but not granddaughters) were greater if the maternal grandmother smoked prenatally: birthweight = +61 95% CI +30, +92 g; birth length = +0.19 95% CI +0.02, +0.35 cm; BMI = +1.6 95% CI +0.6, +2.6 g/m(2). Similar effects were seen in births to primiparae and multiparae. Additional allowance for maternal birthweight resulted in an average increase in boys to +100 g 95% CI +61, +140 g. There were no fetal growth differences if the paternal grandmother had smoked prenatally.
The evidence from this study suggests that when the mother does not smoke in pregnancy the maternal grandmother's smoking habit in pregnancy has a positive association with her grandson's fetal growth.
Birth weight is an important indicator of both perinatal and adult health, but little is known about the genetic factors contributing to its variability. Intrauterine growth restriction is a leading ...cause of perinatal morbidity and mortality and is also associated with adult disease. A significant correlation has been reported between lower birth weight and increased expression of the maternal PHLDA2 allele in term placenta (the normal imprinting pattern was maintained). However, a mechanism that explains the transcriptional regulation of PHLDA2 on in utero growth has yet to be described. In this study, we sequenced the PHLDA2 promoter region in 263 fetal DNA samples to identify polymorphic variants. We used a luciferase reporter assay to identify in the PHLDA2 promoter a 15 bp repeat sequence (RS1) variant that significantly reduces PHLDA2-promoter efficiency. RS1 genotyping was then performed in three independent white European normal birth cohorts. Meta-analysis of all three (total n = 9,433) showed that maternal inheritance of RS1 resulted in a significant 93 g increase in birth weight (p = 0.01; 95% confidence interval CI = 22–163). Moreover, when the mother was homozygous for RS1, the influence on birth weight was 155 g (p = 0.04; 95% CI = 9–300), which is a similar magnitude to the reduction in birth weight caused by maternal smoking.
The authors previously identified a haplotype on chromosome 6p22 defined by three single-nucleotide polymorphisms (SNPs) that was associated with dyslexia (reading disability) in two independent ...samples of families that included at least one sibling with severe reading impairment. The authors also showed that this haplotype is associated with a reduction in expression of the KIAA0319 gene. In addition, a completely independent study detected an association between KIAA0319 markers and reading disability. In the current study, the authors tested whether the KIAA0319 gene influences reading skills in the general population, rather than having an effect restricted to reading disability.
The authors genotyped four SNPs that previously showed association with reading disability in the population of 7-9-year-old children in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large longitudinal cohort for which reading-related phenotypes were available for more than 6,000 individuals. The authors conducted quantitative analysis for both single markers and haplotypes.
The rs2143340 SNP, which effectively tags the three-SNP risk haplotype, was significantly associated with a test for reading ability. The risk haplotype itself also showed association with poor reading performance, and as in previous research, the association was stronger when the analysis was controlled for IQ.
These results both support a role of the KIAA0319 gene in the development of dyslexia and suggest that this gene influences reading ability in the general population. Moreover, the data implicate the three-SNP haplotype and its tagging SNP rs2143340 as genetic risk factors for poor reading performance.
Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In ...pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10−9). rs3757840 was also highly significantly associated with fasting glucose (P=8×10−7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11–53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.
Abstract
Although there are many examples in the experimental literature of an environmental exposure in one generation impacting the phenotypes of subsequent generations, there are few studies that ...can assess whether such associations occur in humans. The Avon Longitudinal Study of Parents and Children (ALSPAC) has, however, been able to determine whether there are associations between grandparental exposures and their grandchildren’s development. Several of our studies, including sensitivity to loud noise, have shown associations between a grandmother smoking in pregnancy and the phenotype of the grandchild. These results were mostly specific to the sex of the grandchild and to whether the prenatal (i.e. during pregnancy) smoking occurred in the maternal or paternal grandmother. Here, we have used ancestral data on prenatal smoking among the grandmothers of the ALSPAC index children to examine possible effects on the grandchild’s ability to detect the bitter taste of PROP (6 n-propylthiouracil), distinguishing between the 10% deemed ‘extreme tasters’, and the rest of the population (total N = 4656 children). We showed that grandchildren whose paternal (but not maternal) grandmothers had smoked in pregnancy were more likely than those of non-smoking grandmothers to be extreme tasters odds ratio (OR) 1.28; 95% confidence interval (CI) 1.03, 1.59 and that this was more likely in granddaughters (OR 1.42; 95% CI 1.03, 1.95) than grandsons (OR 1.18; 95% CI 0.88, 1.60). This pattern of association between paternal foetal exposure and the granddaughter’s development has been found with several other outcomes, suggesting that investigations should be undertaken to investigate possible mechanisms.
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