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Human intelligence, as measured by intelligence quotient (IQ) tests, demonstrates one of the highest heritabilities among human quantitative traits. Nevertheless, studies to identify quantitative trait loci responsible for intelligence face challenges because of the small effect sizes of individual genes. Phenotypically discordant monozygotic (MZ) twins provide a feasible way to minimize the effects of irrelevant genetic and environmental factors, and should yield more interpretable results by finding epigenetic or gene expression differences between twins. Here we conducted array-based genome-wide DNA methylation and gene expression analyses using 17 pairs of healthy MZ twins discordant intelligently. ARHGAP18, related to Rho GTPase, was identified in pair-wise methylation status analysis and validated via direct bisulfite sequencing and quantitative RT-PCR. To perform expression profile analysis, gene set enrichment analysis (GSEA) between the groups of twins with higher IQ and their co-twins revealed up-regulated expression of several ribosome-related genes and DNA replication-related genes in the group with higher IQ. To focus more on individual pairs, we conducted pair-wise GSEA and leading edge analysis, which indicated up-regulated expression of several ion channel-related genes in twins with lower IQ. Our findings implied that these groups of genes may be related to IQ and should shed light on the mechanism underlying human intelligence.

Objective: Interindividual variations in responsiveness to zonisamide in patients with Parkinson's disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD.Methods: We selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of 'wearing-off'. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point.Results: Differentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (Padj=7.8 × 10-3 and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10-3 and 8.2 × 10-3, respectively).Conclusions: Our results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment. [ABSTRACT FROM AUTHOR]

Context: Nonalcoholic fatty liver disease (NAFLD) is becoming a major issue worldwide, even in children. Multiple parallel hits hypothesis has been suggested as progress of NAFLD, but the mechanism of NAFLD is not completely understood. ß-Tubulin is essential in mitoses, neuronal migration, and axon guidance during neuronal development. Pathogenic variants in the TUBB3 gene were shown to be associated with a wide spectrum of neurological abnormalities, but not accompanied by hepatic complications, such as NAFLD. Objective: This work aims to examine the association between TUBB3 mutation and nonalcoholic steatohepatitis (NASH). Methods: An 11-year-old girl has been followed up as having atypical Möbius syndrome since infancy, as she was born with bilateral ptosis, paralytic strabismus, and facial weakness. At age 7 years, she was diagnosed with TUBB3 E410K syndrome by wholeexome sequencing. At age 10 years, her blood examination revealed elevated liver transaminase levels, which persisted for almost 2 years. She underwent liver biopsy, the results of which were suggestive of NASH. Results: The expression of TUBB3 was absent, but that of tyrosine hydroxylase (TH) was present in the parenchymal nerve fibers of the liver. On the other hand, in comparison with an autopsy case of NASH and a normal control, these showed coexpression of TUBB3 and TH in the liver. Conclusion: We report the first case of TUBB3 E410K syndrome accompanied by NASH. This case suggests that the TUBB3 mutation may be associated with the pathogenesis and progression of NASH in humans. [ABSTRACT FROM AUTHOR]

Uterine fibroids are a common benign tumor of the female genital tract. We conducted a genome-wide association study in which 457,044 SNPs were analyzed in 1,607 individuals with clinically diagnosed uterine fibroids and 1,428 female controls. SNPs showing suggestive associations (P < 5 × 10−5) were further genotyped in 3,466 additional cases and 3,245 female controls. Three loci on chromosomes 10q24.33, 22q13.1 and 11p15.5 revealed genome-wide significant associations with uterine fibroids. The SNPs showing the most significant association in a combination analysis at each of these loci were rs7913069 (P = 8.65 × 10−14, odds ratio (OR) = 1.47), rs12484776 (P = 2.79 × 10−12, OR = 1.23) and rs2280543 (P = 3.82 × 10−12, OR = 1.39), respectively. Subsequent fine mapping of these regions will be necessary to pinpoint the causal variants. Our findings should shed light on the pathogenesis of uterine fibroids. [ABSTRACT FROM AUTHOR]

Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case–control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (PFisher<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed PFisher=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (PFisher=0.000237; PCorrected=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression. [ABSTRACT FROM AUTHOR]

Gamma-glutamyl carboxylase ( GGCX) plays an important role in blood coagulation through post-translational carboxylation of vitamin K-dependent blood-clotting proteins. This carboxylation process is impaired in the presence of warfarin, a vitamin K antagonist. Recent studies on GGCX have provided insights into association of polymorphisms in this gene, with inter-individual differences in the required warfarin maintenance dose. In order to provide a useful resource for further elucidating this association, we here report a high-resolution single nucleotide polymorphism (SNP) and haplotype maps of an 18-kb genomic region corresponding to the GGCX locus in the Japanese population. Among 41 SNPs, seven insertion/deletion polymorphisms, and a microsatellite polymorphism that we detected by direct sequencing of the DNAs of 96 Japanese individuals who were treated with warfarin, 32 genetic variations have not been reported. Using genotype information from 12 SNPs and the EM algorithm, we estimated haplotypes for this genomic region. Subsequently, we investigated associations of each of these polymorphisms with the warfarin maintenance-dose requirements of 828 Japanese patients, including the 96 patients that were used for DNA sequencing. We found no significant association between the polymorphisms in GGCX and the dose requirement. [ABSTRACT FROM AUTHOR]