Biology subjects

Ueno, S.

Publications and source records attributed to Ueno, S..

21 records · Page 2Linked to original sources

bioRxiv2019

Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

To uncover genetic basis of autosomal recessive retinitis pigmentosa (ARRP), we applied 2-step genome-wide association study (GWAS) in 640 Japanese patients prescreened with targeted re-sequencing. Meta-GWAS identified three independent peaks at P < 5.0x10-8, all within the major ARRP gene EYS. Two were each tagged by a low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a presumably hypomorphic non-synonymous variant (c.2528G>A, p.G843E). c.2528G>A newly solved 7.0% of Japanese ARRP cases, improving genetic diagnosis by 26.8% and simultaneously serving as a new attractive target for genome editing gene therapy. The third peak was tagged by an intronic common variant, representing a novel disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare "monogenic" disorder for the first time, which provided unexpected insights into significant contribution of non-Mendelian genetic factors and identified a novel high frequency variant directly linked to development of local genome therapeutics.

genetics↗

bioRxiv2019

Group-Level Analysis of Induced Electric Field in Deep Brain Regions by Different TMS Coils

Deep transcranial magnetic stimulation (dTMS) is a non-invasive technique used in treating depression. In this study, we computationally evaluate group-level dosage during dTMS with the aim of characterizing targeted deep brain regions to overcome the limitation of using individualized head models to characterize coil performance in a population.\n\nWe use an inter-subject registration method adapted to deep brain regions that enable projection of computed electric fields (EFs) from individual realistic head models (n = 18) to the average space of deep brain regions. The computational results showed consistent group-level hotspots of the EF in deep brain region with intensities between 20%-50% of the maximum EF in the cortex. Large co-activation in other brain regions was confirmed while half-value penetration depth from the cortical surface was smaller than 2 cm. The halo figure-8 assembly and halo circular assembly coils induced the highest EFs for caudate, putamen, and hippocampus.\n\nGeneralized induced EF maps of deep regions show target regions despite inter-individual difference. This is the first study that visualizes generalized target regions during dTMS and provides a method for making informed decisions during dTMS interventions in clinical practice.

biophysics↗

bioRxiv2018

Frequent variants in the Japanese population determine quasi-Mendelian inheritance of rare retinal ciliopathy

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e. a 3.5-fold enrichment; p-value = 9.2x10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation, in trans with the Alu insertion, but might also cause disease in association with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

genomics↗