The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth ...weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene
TCF7L2 in birth weight. We genotyped the polymorphism
rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval CI 7–29 g) increase in birth weight (
P=.001) and each maternal copy with a 30-g (95% CI 15–45 g) increase in offspring birth weight (
P=2.8×10
−5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g 95% CI 9–48 g increase per allele; corrected
P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ∼0.15 standard deviation;
P=1×10
−4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the −30G→A polymorphism of glucokinase (
rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62–172 g) heavier than were the 32% born to mothers with none (for overall trend,
P=2×10
−7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes–susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.
A number of studies have assessed ages of parents of children with autistic spectrum disorders (ASD), and reported both maternal and paternal age effects. Here we assess relationships with ...grandparental ages.
We compared the parental and grandparental ages of children in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC), according to their scores in regard to 4 autistic trait measures and whether they had been given a diagnosis of ASD. Mean maternal and paternal ages of ASD cases were raised, but this appears to be secondary to a maternal grandmother age effect (P = 0.006): OR = 1.6695%CI 1.16, 2.37 for each 10-year increase in the grandmother's age at the birth of the mother. Trait measures also revealed an association between the maternal grandmother's age and the major autistic trait-the Coherence Scale (regression coefficient b = 0.142, 95%CI = 0.057, 0.228P = 0.001). After allowing for confounders the effect size increased to b = 0.21795%CI 0.125, 0.308(P<0.001) for each 10 year increase in age.
Although the relationship between maternal grandmother's age and ASD and a major autistic trait was unexpected, there is some biological plausibility, for the maternal side at least, given that the timing of female meiosis I permits direct effects on the grandchild's genome during the grandmother's pregnancy. An alternative explanation is the meiotic mismatch methylation (3 M) hypothesis, presented here for the first time. Nevertheless the findings should be treated as hypothesis generating pending corroborative results from other studies.
Functionally relevant polymorphisms of the β2-adrenoceptor gene (
ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We ...aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the
ADRB2 gene.
The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the
ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the
ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses.
Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to
ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36·3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44·6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16–Gln27 haplotype at these loci, 19·3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11·9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1·5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies.
ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population.
It is assumed that the oxytocin receptor gene (OXTR) is associated with factors that are related to features of reproduction as well as the currently emerging fields of mood and emotional response.
...We analysed data from over 8000 mothers who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC). We determined reproductive, emotional and personality differences related to the two SNPs rs53576 and rs2254298 of the oxytocin receptor gene to determine whether there was evidence in this population for: (i) associations with emotional and personality differences, and (ii) behavioural or environmental links with these SNPs using a hypothesis free approach with over 1000 types of exposure.
Our analyses of 7723 women showed that there were no differences in 11 mood, social or relationship characteristics associated with the rs2254298, and just one with rs53576 (with emotional loneliness)--one statistically significant out of 22 tests is no more than would be expected by chance. There were no interactions with childhood abuse. Using a hypothesis-free approach we found few indicators of environmental or behavioural differences associated with rs2254298, but there was an excess of associations with eating habits with rs53576. The findings included an association with dieting to lose weight, and habits typical of bulimia for the women with GG. The nutrition of the women also showed negative associations of the GG genotype with 13 nutrients, including vitamins D, B12 and retinol, and intake of calcium, potassium and iodine.
We conclude that this large database of pregnant women was unable to provide confirmation of the types of personality associated with these two OXTR SNPs, but we have shown some evidence of eating differences in those with GG on rs53576. Confirmation of our hypothesis free associations using other data sets is important.
Previous studies using the Avon Longitudinal Study of Parents and Children (ALSPAC) have shown that if men commenced smoking prior to the onset of puberty their sons, their granddaughters and ...great-granddaughters were more likely to have excess fat (but not lean) mass during childhood, adolescence and early adulthood. In this study we assess associations between ancestral smoking during adolescence (ages 11-16 years) with fat and lean mass of subsequent generations at two ages.
We analysed data on exposures of grandparents and great-grandparents collected by ALSPAC. The outcomes were the fat masses of their grandchildren and great-grandchildren measured at ages 17 and 24. Measures of lean mass were used as controls. Adjustment was made for 8-10 demographic factors using multiple regression.
We found associations between adolescent smoking of the
grandfathers and the adjusted fat mass of their grandchildren, but no associations with the grandchildren's lean mass. Grandchildren at age 17 had an average excess fat mass of +1.65 95% CI +0.04, +3.26 Kg, and at age 24 an average excess of +1.55 95% CI -0.27, +3.38 Kg. Adolescent smoking by the
grandfather showed similar, but weaker, associations: at 17 an average excess fat mass of +1.02 Kg 95% CI -0.20, +2.25 Kg, and at 24 an average excess of +1.28 95% CI -0.11, +2.66 Kg. There were no pronounced differences between the sexes of the children. For the great-grandparents there were few convincing results, although numbers were small.
We have shown associations between grandfathers' smoking in adolescence and increased fat (but not lean) mass in their children. Confirmation of these associations is required, either in a further data set or by demonstrating the presence of supportive biomarkers.
Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin ...studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.
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