See article vol. 28: 338-348 In this issue, the JACC Study group provides a report regarding the relationship between body mass index and mortality from aortic aneurysm and dissection. As the ...absolute risk of aortic aneurysm or dissection was not high enough, collecting Japanese evidence regarding mortality from aortic aneurysm and dissection was difficult. It requires studies with a large sample size and longer follow-up.
Obesity is a risk factor for a wide variety of health problems. In a genome-wide association study (GWAS) of body mass index (BMI) in Japanese people (n = 173,430), we found 85 loci significantly ...associated with obesity (P < 5.0 × 10
), of which 51 were previously unknown. We conducted trans-ancestral meta-analyses by integrating these results with the results from a GWAS of Europeans and identified 61 additional new loci. In total, this study identifies 112 novel loci, doubling the number of previously known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory marks, we found enrichment of variants in CD19
cells. We also found significant genetic correlations between BMI and lymphocyte count (P = 6.46 × 10
, r
= 0.18) and between BMI and multiple complex diseases. These findings provide genetic evidence that lymphocytes are relevant to body weight regulation and offer insights into the pathogenesis of obesity.
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IJS, NUK, SBMB, UL, UM, UPUK
Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and ...low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; P
< 2.5 × 10
). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations.
Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a ...gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
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.
To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ...ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10
) with 115 independent signals (P < 5.0 × 10
), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r
> 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAF
> 0.05 versus MAF
< 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We sought to investigate the optimal values of BMI for the lowest risk of all-cause death and whether the optimal BMI differs according to smoking status in large-scale pooled analysis of 13 Japanese ...cohorts.
Data from 179,987 participants of 13 well-qualified cohort studies conducted throughout Japan were used for our analysis. A cohort-stratified Cox proportional hazard model was used. P values for interactions were calculated based on the cross product of BMI and age, sex, or smoking status.
In the entire study population, all-cause mortality risk was lowest when the BMI was 22.0-24.9 kg/m
. This was also the case for selected healthy participants (never smoked, baseline total cholesterol level ≥4.1 mmol/L; the first 5 years of follow-up data were excluded). No effect modification of age, sex, or smoking status was observed. Regardless of their BMI, never smokers always had a lower all-cause mortality risk than did current smokers even with an ideal BMI in terms of mortality risk.
A BMI of 22-24.9 kg/m
correlated with the lowest risk of mortality, regardless of whether all participants or selected healthy participants were analyzed. The fact that smoking was more strongly associated with mortality than obesity emphasizes the urgency for effective anti-smoking programs.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
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.
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