Marcus Pembrey

Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4

Deafness with fixation of the stapes (DFN3) is the most frequent X-linked form of hearing impairment. The underlying gene has been localized to a 500-kilobase segment of the Xq21 band. Here, it is reported that a candidate gene for this disorder, Brain 4 (POU3F4), which encodes a transcription factor with a POU domain, maps to the same interval. In five unrelated patients with DFN3 but not in 50 normal controls, small mutations were found that result in truncation of the predicted protein or in nonconservative amino acid substitutions. These findings indicate that POU3F4 mutations are a molecular cause of DFN3.

Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms

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-2R alpha) 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=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-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.

Uniparental paternal disomy in Angelman's syndrome

Angelmans syndrome and Prader-Willi syndrome are both causes of mental retardation with recognisable, but quite different, clinical phenotypes. Both are associated with deletions of chromosome 15q11-13, of maternal origin in Angelmans and paternal in Prader-Willi. Prader-Willi can arise by inheritance of two chromosomes 15 from the mother and none from the father (uniparental maternal disomy). In 2 patients with Angelmans syndrome we found evidence of uniparental paternal disomy. The phenotypic effects of maternal and paternal disomy of chromosome 15 are very different and inheritance of two normal 15s from one parent does not lead to normal development--strong evidence in man for genomic imprinting, in which the same gene has different effects dependent upon its parental origin.

Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects.

We studied 270 Saudi Arabs with homozygous sickle cell anemia, using chart review, a register (since 1969), and home visiting in 42 cases. Average follow-up for the total group was 10 years. Seventy-four percent of those diagnosed by age 3 years presented on screening or with merely anemia; 26% presented with illness, abnormal physical findings, or pain. Compared with American or Jamaican blacks, serious complications occurred only 6% to 25% as frequently; leg ulcers did not occur at all; the mortality under age 15 years was 10% as great; mean levels of blood hemoglobin were higher (10 g/dl), reticulocyte count was lower (5% to 6%), and mean fetal hemoglobin (HbF), which was inversely correlated with reticulocytes, was higher (22% to 26.8%). The high HbF is believed to account for the very mild clinical manifestations.

Male-line transgenerational responses in humans

Genomic imprinting establishes the principle of epigenetic marks placed in one generation influencing gene expression in the next generation. This led to speculation that epigenetic gametic inheritance might underlie a form of transgenerational adaptation to major environmental challenges, such that exposures in one generation correlate with outcomes in the next generation(s). An ongoing collaboration between Umeå University, Sweden and the Avon Longitudinal Study of Parents and Childhood, Bristol University, UK has documented transgenerational correlations between food supply during the early life of the paternal grandparents and the grandchilds longevity, including associations with cardiovascular and diabetic deaths, and correlations between the onset of paternal smoking in mid-childhood and the body mass index of future sons. Whilst the mediating molecular mechanism(s) is unknown, the sex-specific transmission patterns and exposure-sensitive periods suggest a pre-evolved transgenerational response mechanism.

Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research

Mammalian experiments provide clear evidence of male line transgenerational effects on health and development from paternal or ancestral early-life exposures such as diet or stress. The few human observational studies to date suggest (male line) transgenerational effects exist that cannot easily be attributed to cultural and/or genetic inheritance. Here we summarise relevant studies, drawing attention to exposure sensitive periods in early life and sex differences in transmission and offspring outcomes. Thus, variation, or changes, in the parental/ancestral environment may influence phenotypic variation for better or worse in the next generation(s), and so contribute to common, non-communicable disease risk including sex differences. We argue that life-course epidemiology should be reframed to include exposures from previous generations, keeping an open mind as to the mechanisms that transmit this information to offspring. Finally, we discuss animal experiments, including the role of epigenetic inheritance and non-coding RNAs, in terms of what lessons can be learnt for designing and interpreting human studies. This review was developed initially as a position paper by the multidisciplinary Network in Epigenetic Epidemiology to encourage transgenerational research in human cohorts.

A Common Haplotype of the Glucokinase Gene Alters Fasting Glucose and Birth Weight: Association in Six Studies and Population-Genetics Analyses

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=8x10-7), 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.

Association of the KIAA0319 Dyslexia Susceptibility Gene With Reading Skills in the General Population

OBJECTIVE 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. METHOD 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. RESULTS 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. CONCLUSIONS 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.

Time to take epigenetic inheritance seriously

Rich pickings from the past Any study of transgenerational effects needs information from across the generations, and this is not easy to obtain in humans. There is little research on the effect of exposures in grandparents on outcomes in their grandchildren, but one such study, reported on pages 682 – 688 of this issue, obliges us to confront the possibility of epigenetic inheritance down the male line. Herein lies the importance for human geneticists of the work of Kaati, Bygren and Edvinsson from Umea University, Sweden. Building on their interest in early nutritional influences on cardiovascular mortality, they have exploited records of annual harvests from an isolated community in northern Sweden that go back as far as 1799 to explore the effects of food availability across three generations. Earlier work by the team on a cohort born in 1905 showed a remarkable effect of food availability during the slow growth period (SGP) just before puberty of the paternal grandfather on the longevity of the probands. Scarcity of food in grandfather’s SGP was associated with a significantly extended survival of his grandchildren for many years, whilst food abundance was associated with a greatly shortened life span of the grandchildren. There are only four possible explanations; chromosomal transmission of nutritionally-induced epigenetic modifications, intense genetic selection through differential survival /fertility, a statistical quirk or hidden bias producing a false association, or some mechanism of inheritance yet to be discovered. In the present study Kaati and colleagues have enlarged the sample with two new cohorts born in 1890 and 1920 in order to have the power to look specifically at cardiovascular and diabetes related deaths. The latter outcome was chosen because imprinted genes have been implicated in diabetes risk. The first thing to say is that the shorter survival of probands when the paternal grandfather had been exposed to plenty of food during his SGP was replicated in the newly studied 1890 cohort, although this association could not be demonstrated in the 1920 cohort. Overall they show that cardiovascular mortality was reduced with poor availability of food in the father’s SGP, but also with good availability in the mother’s SGP. This reciprocal effect of parental nutrition is intriguing in itself, but the most striking result comes with diabetes. If the paternal grandfather was exposed to a surfeit of food during his SGP, then the proband had a fourfold excess mortality related to diabetes (OR 4.1, 95% c.i.1.33 – 12.93, P=0.01) when age at death and the effects of possible over eating among parents and grandparents during their respective SGP were taken into account. Interestingly a father’s exposure to a surfeit of food during his SGP tended to protect the proband from diabetes (OR 0.13, 95% c.i. 0.02 – 1.07, P=0.06), hinting at some ‘see-saw’ effect down the generations. The more unexpected the result, the more important it is to replicate the findings on other cohorts. This should be possible in northern Sweden thanks, in part, to the regional harvest records that were demanded by His Majesty the King in times gone by.

Type 2 Diabetes TCF7L2 Risk Genotypes Alter Birth Weight: A Study of 24,053 Individuals

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=2.8x10-5). 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=1x10-4), 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=2x10-7), 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.