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The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies. The Tohoku Medical Megabank Organization establishes a biobank with detailed patient health care and genome information. Here the authors analyse whole-genome sequences of 1,070 Japanese individuals, allowing them to catalogue 21 million single-nucleotide variants including 12 million novel ones.

Purpose To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. Study design Molecular genetic analysis. Methods Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B , FOXC1 , and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). Results For CYP1B1 , we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1- , FOXC1- , and MYOC- negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. Conclusions Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.

Purpose To determine whether non-invasive measurements of the nailfold capillaries (NCs) are associated with the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes. Methods Eighty-three eyes of 83 patients with type 2 diabetes were enrolled. Sixty-three age-matched non-diabetic subjects served as controls. Diabetic patients were classified by the severity of their DR: non-DR (NDR), non-proliferative DR (NPDR), and proliferative DR (PDR). We used nailfold capillaroscopy to measure NC parameters, including number, length, width, and turbidity. Results Four NC parameters in the diabetic patients were significantly lower than in the controls (all P  < 0.001). There was a statistically significant decrease in the NC parameters along with the increasing severity of DR (number: P  = 0.02; all others: P  < 0.001). Logistic regression analysis revealed that combining the systemic characteristics of age, sex, systolic blood pressure, estimated glomerular filtration rate, hemoglobin A1c level, and history of hypertension and dyslipidemia could indicate the presence of DR and PDR (the area under the receiver operating characteristic curve [AUC] = 0.81, P  = 0.006; AUC = 0.87, P  = 0.001, respectively). Furthermore, the discriminative power of DR was significantly improved ( P  = 0.03) by adding NC length to the systemic findings (AUC = 0.89, P  < 0.001). Conclusion NC measurement is a simple and non-invasive way to assess the risk of DR and its severity.

BackgroundNatural disasters may have negative health effects on survivors. However, long-term observations on this are lacking. Therefore, this study investigated the association between the degree of housing damage caused by the Great East Japan Earthquake (GEJE) and all-cause mortality using the data from the cohort study conducted by the Tohoku Medical Megabank (TMM) Project in disaster-stricken areas.MethodsThe community-based cohort study of the TMM Project which conducted a baseline survey from May 2013 to March 2016 collected data using questionnaires and blood and urine tests. The present large-scale prospective cohort study was a follow-up survey in which the degree of house damage and all-cause mortality were analysed using Cox proportional hazards regression, adjusting for sex, age and other potentially confounding variables. The degree of house damage was categorised into ‘did not live in the disaster area’, ‘no damage’, ‘small-scale damage’ and ‘large-scale damage’. Among the 58 320 participants, 1763 deaths were confirmed during the follow-up which averaged 6.5 years.ResultsThe multivariate analysis showed a hazard ratio (95% CI) of 0.96 (0.82 to 1.13) for those who did not live in the disaster area, 0.98 (0.87 to 1.10) for small-scale damage and 0.98 (0.85 to 1.14) for large-scale damage, compared with no damage, but no significant association with all-cause mortality was observed.ConclusionThe results of this large-scale prospective cohort study of GEJE survivors showed no significant relationship between the degree of house damage and all-cause mortality. Further long-term follow-up studies are needed to examine the long-term health effects of natural disasters on survivors.

This study aimed to examine whether risk of withdrawal from HTTx was higher in coastal areas that were severely damaged by tsunami than in inland areas. We conducted a cross-sectional study of 9218 participants aged ≥20 years in Miyagi, Japan. The odds ratios (ORs) and confidence interval (CI) for withdrawal from HTTx in coastal and inland groups were compared using multivariate logistic regression analysis, adjusting for potential confounders. In total, 194 of 5860 and 146 of 3358 participants in the inland and coastal groups, respectively, withdrew from HTTx treatment. OR (95%CI) of withdrawal from HTTx in the coastal group was 1.46 (1.14–1.86) compared to the inland group. According to housing damage, ORs (95% CI) in the no damage, partially destroyed, and more than half destroyed coastal groups compared with the no damage inland group were 1.62 (1.04–2.50), 1.69 (1.17–2.45), and 1.08 (0.71–1.65), respectively. In conclusion, the risk of HTTx withdrawal for participants whose homes in coastal areas were relatively less damaged was significantly higher compared with those in inland areas, while the risk of HTTx withdrawal for participants whose homes were more than half destroyed was not. Post-disaster administrative support for disaster victims is considered vital for continuation of their treatment.

Age-related hearing loss (ARHL) has a multifactorial pathogenesis, and the influence of alcohol consumption on it is controversial. This cross-sectional study investigated the association between ARHL and alcohol consumption by using cohort data from Tohoku Medical Megabank Project, including self-reported questionnaires and pure-tone audiometry thresholds (500, 1000, 2000, and 4000 Hz). ARHL was defined as a threshold of > 25 dB in the better ear. Multiple logistic regression analyses (age 50–79 y; 5,219 men and 9,266 women) were conducted separately for men and women and indicated that daily alcohol consumption levels of 60–80 and ≥ 80 g were significantly associated with increased odds of ARHL at 4,000 Hz in men (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.05–1.94; OR 1.55; 95% CI 1.12–2.16; respectively); consumption of 10–20 g was significantly associated with reduced odds of ARHL at 4,000 Hz in women (OR 0.81; 95% CI 0.68–0.96). Assessment of drinking-related single nucleotide polymorphisms suggested that the effect of alcohol on ARHL may differ by genotype. Our findings suggest a sex-specific association between alcohol consumption and ARHL; heavy drinking is a potential risk factor in men, whereas moderate drinking may have a protective effect in women.

Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2 , is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.

The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels with easy-to-use interfaces. In the Tohoku Medical Megabank Project, we sequenced nearly 4000 individuals from a Japanese population and constructed an allele frequency panel of 3552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first large-scale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.Population genetics: large database of Japanese gene variations constructedA new database provides information on the frequency of genetic variations within 3552 Japanese individuals, and facilitates comparisons with other populations. The reference panel, constructed by Kengo Kinoshita of Tohoku University, Sendai, and colleagues in Japan is also the first large-scale database to provide genetic variation frequency information on the X chromosome and mitochondrial DNA in the Japanese population. The methods used to sequence the genetic data are similar to those used in other large databases, allowing comparisons with other populations. The population size and methods used to compile the database overcome limitations in previous Japanese reference panels. This and similar databases that catalog genetic variations within populations can improve efforts towards personalizing healthcare and contribute to the study of human population genetics. The database is publicly available online.

Few population-based studies including younger adults have examined the potential of olfactory function tests to capture the degree of atrophy in memory-associated brain regions, which cannot be adequately explained by cognitive function tests screening for cognitive impairment. This population-based study investigated associations between high-resolution olfactory test data with few odours and grey matter volumes (GMVs) of the left and right hippocampi, amygdala, parahippocampi, and olfactory cortex, while accounting for differences in cognitive decline, in 1444 participants (aged 31–91 years). Regression analyses included intracranial volume (ICV)-normalised GMVs of eight memory-related regions as objective variables and age, sex, education duration, smoking history, olfaction test score, and the Montreal Cognitive Assessment-Japanese version (MoCA-J) score as explanatory variables. Significant relationships were found between olfactory test scores and ICV-normalised GMVs of the left and right hippocampi and left amygdala ( p  = 0.020, 0.024, and 0.028, respectively), adjusting for the MoCA-J score. The olfactory test score was significantly related to the right amygdalar GMV ( p  = 0.020) in older adults (age ≥ 65 years). These associations remained significant after applying Benjamini–Hochberg multiple testing correction (false discovery rate < 0.1). Therefore, olfactory and cognitive function tests may efficiently capture the degree of atrophy in the hippocampi and amygdala, especially in older adults.