Handedness in twins: Joint analysis of data from 35 samples

Simultaneous analysis of handedness data from 35 samples of twins (with a combined sample size of 21,127 twin pairs) found a small but significant additive genetic effect accounting for 25.47% of the variance (95% confidence interval [CI] 15.69-29.51%). No common environmental influences were detected (C = 0.00; 95% Cl 0.00-7.67%), with the majority of the variance, 74.53%, explained by factors unique to the individual (95% Cl 70.49-78.67%). No significant heterogeneity was observed within studies that used similar methods to assess handedness, or across studies that used different methods. At an individual level the majority of studies had insufficient power to reject a purely unique environmental model due to insufficient power to detect familial aggregation. This lack of power is seldom mentioned within studies, and has contributed to the misconception that twin studies of handedness are not informative.

Increased DNA Methylation at the AXIN1 Gene in a Monozygotic Twin from a Pair Discordant for a Caudal Duplication Anomaly

The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic ( MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated than that of the unaffected twin (), which was significantly more P < .0001 methylated than those of the controls (). We have confirmed that this CpG island does function as a promoter P = .02 in vitro and that its activity is inversely proportional to the extent of methylation. This finding raises the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. This case may be paradigmatic for some cases of MZ discordance.

A simple method to localise pleiotropic susceptibility loci using univariate linkage analyses of correlated traits

Univariate linkage analysis is used routinely to localise genes for human complex traits. Often, many traits are analysed but the significance of linkage for each trait is not corrected for multiple trait testing, which increases the experiment-wise type-I error rate. In addition, univariate analyses do not realise the full power provided by multivariate data sets. Multivariate linkage is the ideal solution but it is computationally intensive, so genome-wide analysis and evaluation of empirical significance are often prohibitive. We describe two simple methods that efficiently alleviate these caveats by combining P-values from multiple univariate linkage analyses. The first method estimates empirical pointwise and genome-wide significance between one trait and one marker when multiple traits have been tested. It is as robust as an appropriate Bonferroni adjustment, with the advantage that no assumptions are required about the number of independent tests performed. The second method estimates the significance of linkage between multiple traits and one marker and, therefore, it can be used to localise regions that harbour pleiotropic quantitative trait loci (QTL). We show that this method has greater power than individual univariate analyses to detect a pleiotropic QTL across different situations. In addition, when traits are moderately correlated and the QTL influences all traits, it can outperform formal multivariate VC analysis. This approach is computationally feasible for any number of traits and was not affected by the residual correlation between traits. We illustrate the utility of our approach with a genome scan of three asthma traits measured in families with a twin proband.

Rapid screening of 4000 individuals for germ-line variations in the BRAF gene

Background: The BRAF gene is frequently somatically altered in malignant melanoma. A majority of variations are at the valine 600 residue leading to a V600E substitution that constitutively activates the kinase. We screened 4000 patient and control DNAs for germ-line variations at the valine 600 residue. Methods: We developed a novel assay by adapting single-base variation assays and software for MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry to screen for all 5 reported variants at codon 600 of the BRAF gene. We screened a case-control collection comprising samples from 1082 melanoma patients and 154 of their unaffected relatives from 1278 families and from 2744 individuals from 659 unselected twin families with no history of melanoma. A panel of 66 melanoma cell lines was used for variation-positive controls. Results: All melanoma cell lines that we had found previously to carry a codon 600 variation were verified in this study. Three of the 4 possible variants (V600E n = 47, V600K n = 2, V600R n = 1) were detected, but no case of V600D was available. No germ-line variants were found in the samples from the 3980 melanoma patients or from the control individuals. Conclusions: This new assay is a high-throughput, automated alternative to standard sequencing and can be used as a rapid initial screen for somatic variants associated with melanoma. Germ-line variants at valine 600 are unlikely to exist and do not contribute to the reported role of the BRAF gene in melanoma predisposition. (c) 2006 American Association for Clinical Chemistry.

Novel variants in growth differentiation factor 9 in mothers of dizygotic twins

Context: Genes from the ovarian bone morphogenetic signaling pathway (GDF9 and BMP15) are critical for normal human fertility. We previously identified a deletion mutation in GDF9 in sisters with spontaneous dizygotic (DZ) twins, but the prevalence of rare GDF9 variants in twinning families is unknown. Objective: The objective was to evaluate the frequency of rare variants in GDF9 in families with a history of DZ twinning. Design and Subjects: We recruited 3450 individuals from 915 DZ twinning families (1693 mothers of twins) and 1512 controls of Caucasian origin. One mother of DZ twins was selected from 279 of the 915 families, and a DNA sample was screened for rare variants in GDF9 using denaturant HPLC. Variants were confirmed by DNA sequencing and genotyped in the entire sample by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. Results: We found two novel insertion/deletions (c.392-393insT, c.1268-1269delAA) and four missense alterations in the GDF9 sequence in mothers of twins. Two of the missense variants (c.307C > T, p.Pro103Ser and c.362C > T, p.Thr121Leu) were located in the proregion of GDF9 and two (c.1121C > T, p.Pro374Leu and c.1360C > T, p.Arg454Cys) in the mature protein region. For each variant, the frequencies were higher in cases compared with controls. The proportion of mothers of DZ twins carrying any variant (4.12%) was significantly higher (P < 0.0001) than the proportion of carriers in controls (2.29%). Conclusion: We describe new variants in the GDF9 gene that are significantly more common in mothers of DZ twins than controls, suggesting that rare GDF9 variants contribute to the likelihood of DZ twinning.

HLA and Genomewide Allele Sharing in Dizygotic Twins

Gametic selection during fertilization or the effects of specific genotypes on the viability of embryos may cause a skewed transmission of chromosomes to surviving offspring. A recent analysis of transmission distortion in humans reported significant excess sharing among full siblings. Dizygotic (DZ) twin pairs are a special case of the simultaneous survival of two genotypes, and there have been reports of DZ pairs with excess allele sharing around the HLA locus, a candidate locus for embryo survival. We performed an allele-sharing study of 1,592 DZ twin pairs from two independent Australian cohorts, of which 1,561 pairs were informative for linkage on chromosome 6. We also analyzed allele sharing in 336 DZ twin pairs from The Netherlands. We found no evidence of excess allele sharing, either at the HLA locus or in the rest of the genome. In contrast, we found evidence of a small but significant (P = .003 for the Australian sample) genomewide deficit in the proportion of two alleles shared identical by descent among DZ twin pairs. We reconciled conflicting evidence in the literature for excess genomewide allele sharing by performing a simulation study that shows how undetected genotyping errors can lead to an apparent deficit or excess of allele sharing among sibling pairs, dependent on whether parental genotypes are known. Our results imply that gene-mapping studies based on affected sibling pairs that include DZ pairs will not suffer from false-positive results due to loci involved in embryo survival.

Linkage analyses of event-related potential slow wave phenotypes recorded in a working memory task

Working memory is an essential component of wide-ranging cognitive functions. It is a complex genetic trait probably influenced by numerous genes that individually have only a small influence. These genes may have an amplified influence on phenotypes closer to the gene action. In this study, event-related potential (ERP) phenotypes recorded during a working-memory task were collected from 656 adolescents from 299 families for whom genotypes were available. Univariate linkage analyses using the MERLIN variance-components method were conducted on slow wave phenotypes recorded at multiple sites while participants were required to remember the location of a target. Suggestive linkage (LOD > 2.2) was found on chromosomes 4, 5, 6, 10, 17, and 20. After correcting for multiple testing, suggestive linkage remained on chromosome 10. Empirical thresholds were computed for the most promising phenotypes. Those on chromosome 10 remained suggestive. A number of genes reported to regulate neural differentiation and function (i.e. NRP1, ANK3, and CHAT) were found under these linkage peaks and may influence the levels of neural activity occurring in individuals participating in a spatial working-memory task.

Further evidence of linkage at 7p22 with familial hyperaldosteronism type II and exclusion of genetic defects in the RBAK coding regions

Once thought rare, primary aldosteronism (PAL) is now reported to be responsible for 5–10% of hypertension. Unlike familial hyperaldosteronism type I (FH-I), FH-II is not glucocorticoidremediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. At least five times more common than FH-I, FH-II is clinically indistinguishable from apparently sporadic PAL, suggesting an even higher incidence. Studies performed in collaboration with C Stratakis (NIH, Bethesda) on our largest Australian family (eight affected members) demonstrated linkage at chromosome 7p22. Linkage at this region was also found in a South American family (DNA provided by MI New, Mount Sinai School of Medicine, New York) and in a second Australian family. The combined multipoint LOD score for these 3 families is 4.61 (q = 0) with markers D7S462 and D7S517, providing strong support for this locus harbouring mutations responsible for FH-II. A newly identified recombination event in our largest Australian family has narrowed the region of linkage by 1.8 Mb, permitting exclusion of approximately half the genes residing in the originally reported 5 Mb linked locus. Candidate genes that are involved in cell cycle control are of interest as adrenal hyperplasia and adrenal adenomas are common in FH-II patients. A novel candidate gene in this linked region produces the retinoblastoma-associated Kruppel-associated box protein (RBaK) which interacts with the retinoblastoma gene product to repress the expression of genes activated by members of the E2F family of transcription factors.

Transglutaminase inhibition ameliorates experimental diabetic nephropathy

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.

Group work and cognitive style:a discursive investigation

This article investigates the relationship between work-group members’ cognitive style (as measured by Allinson and Hayes’s Cognitive Style Index), the group’s task and setting, and the way in which group members behave in the group. Behavior of a homogeneous analytic, a homogeneous intuitive, and a heterogeneous group was observed in a mechanistic setting and analyzed using discourse analysis. This study is discussed in light of a previous study in which homogeneous analytic and homogeneous intuitive groups worked in an organic setting. These two studies use different methodologies (quantitative approach versus qualitativediscursive). The benefits of methodological eclecticism are discussed.

Radiation effects in metal-oxide-semiconductor capacitors

An investigation has been undertaken into the effects of various radiations on commercially made Al-SiO2-Si Capacitors (MOSCs). Detailed studies of the electrical and physical nature of such devices have been used to characterise both virgin and irradiated devices. In particular, an investigation of the nature and causes of dielectric breakdown in MOSCs has revealed that intrinsic breakdown is a two-stage process dominated by charge injection in a pre-breakdown stage; this is associated with localised high-field injection of carriers from the semiconductor substrate to interfacial and bulk charge traps which, it is proposed, leads to the formation of conducting channels through the dielectric with breakdown occurring as a result of the dissipation of the conduction band energy. A study of radiation-induced dielectric breakdown has revealed the possibility of anomalous hot-electron injection to an excess of bulk oxide traps in the ionization channel produced by very heavily ionizing radiation, which leads to intrinsic breakdown in high-field stressed devices. These findings are interpreted in terms of a modification to the model for radiation-induced dielectric breakdown based upon the primary dependence of breakdown on charge injection rather than high-field mechanisms. The results of a detailed investigation of charge trapping and interface state generation in such MOSCs due to various radiations has revealed evidence of neutron induced interface states, and of the generation of positive oxide charge in devices due to all of the radiations tested. In particular, the greater the linear energy transfer of the radiation, the greater the magnitude of charge trapped in the oxide and the greater the number of interface states generated. These findings are interpreted in terms of Si-H and Si-OH bond-breaking at the Si-SiO2 interface which is enhanced by charge carrier transfer to the interface and by anomalous charge injection to compensate for the excess of charge carriers created by the radiation.