Hypertensive disorders of pregnancy, neonatal outcomes and offspring developmental delay in Japan: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

INTRODUCTION: Developmental delay at an early age indicates the probability of continued problems after school age. Hypertensive disorders of pregnancy (HDP) are associated with developmental delays in offspring, with inconsistent outcomes. Neonatal outcomes vary according to HDP exposure and are relevant to development in later years. Here we aimed to clarify the relationship between HDP and developmental delay in offspring and whether neonatal outcomes mediate this association. MATERIAL AND METHODS: We used data from 5934 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study conducted in Japan between July 2013 and March 2017. The Ages and Stages Questionnaires, third edition, at 24 and 42 months of age, measured developmental delay in five areas. We performed multivariate quasi-Poisson regression and causal mediation analysis by neonatal outcomes. RESULTS: At 24 months of age, compared to offspring born from normotensive mothers, offspring born from HDP-affected mothers were more likely to experience developmental delay (risk ratio [RR] 1.29, 95% confidence interval [CI]: 1.09-1.52) in the areas of communication (RR 1.21, 95% CI: 1.00-1.45) and personal-social (RR 1.15, 95% CI: 1.03-1.28). This association was mediated by neonatal outcomes: preterm birth, neonatal asphyxia, NICU admission, and neonatal small head circumference. No association was observed between HDP and developmental delay at 42 months of age. CONCLUSIONS: Exposure to HDP during fetal life is associated with offspring developmental delay. This association is partly mediated by neonatal outcomes.

Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.

BACKGROUND: Nausea and vomiting during pregnancy (NVP) and hyperemesis gravidarum (HG), common conditions affecting most pregnant women, are highly heritable and associated with maternal and fetal morbidity. However, the pathologies underlying NVP and HG and their associated loci are scarce. METHODS: We performed genome-wide association studies (GWAS) of NVP in pregnant women (n = 23,040) who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan from July 2013 to March 2017. Participants were divided into discovery (n = 9,464) and replication (n = 10,051) stages based on the platform used for their genotyping. Loci that achieved the genome-wide significance level (p < 5.0 × 10- 8) in the discovery stage were selected for genotyping in the replication stage. A meta-analysis integrating the discovery and replication stage results (n = 19,515) was conducted. NVP-related variables were identified as categorical or continuous. RESULTS: GWAS analysis in the discovery phase revealed loci linked to NVP in two gene regions, 11q22.1 (rs77775955) and 19p13.11 (rs749451 and rs28568614). Loci in these two gene regions have also been shown to be associated with HG in a White European population, indicating the generalizability of the GWAS analyses conducted in this study. Of these, only rs749451 and rs28568614 at 19p13.11 reached the genome-wide suggestive level (p < 1.0 × 10- 5) in the replication stage; however, both loci were significant in the meta-analysis. CONCLUSIONS: NVP-related loci were identified in the Japanese population at 11q22.1 and 19p13.11, as reported in previous GWAS. This study contributes new evidence on the generalizability of previous GWAS on the association between genetic background and NVP.

Association between frequency of breakfast intake before and during pregnancy and developmental delays in children: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

BACKGROUND: Although an association between maternal nutritional intake and developmental delays in children has been demonstrated, the association of the timing of meal intake and development delays remains unclear. We examined the association between breakfast intake frequency before and during pregnancy and developmental delay in children. METHODS: Of the pregnant women who participated in the Tohoku Medical Megabank Project Three-Generation Cohort Study, 7491 answered the required questions and were analyzed. The frequency of breakfast intake from pre- to early pregnancy and from early to mid-pregnancy was classified into four groups: daily, and 5-6, 3-4, and 0-2 times/week. Child developmental delays at age 2 and 3.5 years were assessed using the Ages & Stages Questionnaire, Third Edition. Logistic regression models were constructed to examine the association between breakfast intake frequency in pregnant women and developmental delays in children aged 2 and 3.5 years. RESULTS: The proportion of pregnant women who had breakfast daily was 78.1% in pre- to early pregnancy, and 82.2% in early to mid-pregnancy. The proportion of children with developmental delays was 14.7% and 13.4% at age 2 and 3.5 years, respectively. Compared with the risk in children of women who had breakfast daily from pre- to early pregnancy, children of women who had breakfast 0-2 times/week had a higher risk of developmental delays at 2 years of age: odds ratio (OR) 1.30, (95% confidence interval [CI], 1.02-1.66). The risk of developmental delays at age 2 years increased in the children of women who had breakfast 0-2 times/week in early to mid- pregnancy: OR 1.75 (95% CI, 1.32-2.32). The risk of developmental delays at age 3.5 years did not increase in the children of women who had breakfast 0-2 times/week from pre- to early and early to mid-pregnancy: OR 1.06 (95% CI, 0.81-1.39 and OR 1.15 (95% CI 0.84-1.57), respectively. CONCLUSION: For women with a low frequency of breakfast intake from pre- to mid-pregnancy there was an association with developmental delays in their children at age 2, but not at 3.5 years.

Associations of combined genetic and lifestyle risks with hypertension and home hypertension.

No study, to our knowledge, has constructed a polygenic risk score based on clinical blood pressure and investigated the association of genetic and lifestyle risks with home hypertension. We examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. In a cross-sectional study of 7027 Japanese individuals aged ≥20 years, we developed a lifestyle score based on body mass index, alcohol consumption, physical activity, and sodium-to-potassium ratio, categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score was constructed with the target data (n = 1405) using publicly available genome-wide association study summary statistics from BioBank Japan. Using the test data (n = 5622), we evaluated polygenic risk score performance and examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension and home hypertension were defined as blood pressure measured at a community-support center ≥140/90 mmHg or at home ≥135/85 mmHg, respectively, or self-reported treatment for hypertension. In the test data, 2294 and 2322 participants had hypertension and home hypertension, respectively. Both polygenic risk and lifestyle scores were independently associated with hypertension and home hypertension. Compared with those of participants with low genetic risk and an ideal lifestyle, the odds ratios for hypertension and home hypertension in the low genetic risk and poor lifestyle group were 1.94 (95% confidence interval, 1.34-2.80) and 2.15 (1.60-2.90), respectively. In summary, lifestyle is important to prevent hypertension; nevertheless, participants with high genetic risk should carefully monitor their blood pressure despite a healthy lifestyle.

Ictal chest discomfort in a patient with temporal lobe seizures and amygdala enlargement.

Chest discomfort is the representative symptom of dangerous coronary artery disease (CAD), but rarely occurs in patients with seizures. We treated a 74-year-old man with right mesial temporal lobe epilepsy and amygdala enlargement, who was initially suspected of CAD and underwent repeated cardiac angiography because of recurrent episodes of paroxysmal chest discomfort starting from 68 years old. He visited an epileptologist and underwent long-term video electroencephalography monitoring (LTVEM), which confirmed right temporal seizure onset during a habitual episodes of "chest discomfort," stereotyped movement of chest rubbing with the right hand, followed by impaired conscousness. Brain magnetic resonance imaging revealed right amygdala enlargement. The present case emphasizes the importance of the wide range of symptoms, such as chest discomfort, which may associated with epielpsy and result in a delayed diagnosis. LTVEM is useful for diagnosis of epilepsy with unusual seizure semiology by recording ictal EEG changes during chest discomfort.

Dietary calcium intake was related to the onset of pre-eclampsia: The TMM BirThree Cohort Study.

This study aimed to explore the relationship between dietary electrolyte intake and the prevalence of hypertensive disorders of pregnancy (HDP) subtypes. Our analysis included 19 914 pregnant women from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. A food frequency questionnaire was used to estimate dietary calcium, potassium, sodium, and magnesium intakes. HDP was determined based on the medical records during regular antenatal care. Logistic regression analysis assessed the relationship between dietary electrolytes intake quintiles, and HDP subtypes with adjustment for basic characteristics. Dietary electrolyte intakes were applied for the prediction model. Of the cohort, 547 participants delivered with pre-eclampsia (PE), 278 with superimposed PE (SP), and 896 with gestational hypertension (GH). PE was associated with low crude calcium intake (odds ratio of the first quintile [<251 mg/day] to the fifth quintile [>623 mg/day] and 95% confidence interval, 1.31 [1.00-1.70]) and P for trend was .02. SP was not associated with any nutritional intake; however, the combined outcome of PE and SP was related to low crude calcium and potassium and energy-adjusted calcium, potassium, and magnesium intakes (P for trend, .01, .048, .02, .04, and .02, respectively). The same tendency was observed for GH. A prediction model that included crude calcium and potassium intakes performed better than a model without them. In conclusion, low dietary calcium, potassium, and magnesium were associated with higher HDP subtypes prevalence. The prediction model implied that crude calcium and potassium intakes might play a critical role in PE and SP pathogenesis.

Clustering by phenotype and genome-wide association study in autism.

Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability. We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a data set of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC data set of 712 probands and 354 controls in the replication stage. In the preliminary study, which was conducted in conventional GWAS design, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P < 5.0 × 10-8. Some of these loci were located within or near previously reported candidate genes for ASD: CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5, ITPR1, NTM, SDK1, SNCA, and SRRM4. Of these 65 significant chromosomal loci, rs11064685 located within the SRRM4 gene had a significantly different distribution in the cases vs controls in the replication cohort. These findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.

Relationships among personality traits, metabolic syndrome, and metabolic syndrome scores: The Kakegawa cohort study.

OBJECTIVE: Metabolic syndrome and the presence of metabolic syndrome components are risk factors for cardiovascular disease (CVD). However, the association between personality traits and metabolic syndrome remains controversial, and few studies have been conducted in East Asian populations. METHODS: We measured personality traits using the Japanese version of the Eysenck Personality Questionnaire (Revised Short Form) and five metabolic syndrome components-elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose-in 1322 participants aged 51.1±12.7years old from Kakegawa city, Japan. Metabolic syndrome score (MS score) was defined as the number of metabolic syndrome components present, and metabolic syndrome as having the MS score of 3 or higher. We performed multiple logistic regression analyses to examine the relationship between personality traits and metabolic syndrome components and multiple regression analyses to examine the relationship between personality traits and MS scores adjusted for age, sex, education, income, smoking status, alcohol use, and family history of CVD and diabetes mellitus. We also examine the relationship between personality traits and metabolic syndrome presence by multiple logistic regression analyses. RESULTS: "Extraversion" scores were higher in those with metabolic syndrome components (elevated waist circumference: P=0.001; elevated triglycerides: P=0.01; elevated blood pressure: P=0.004; elevated fasting glucose: P=0.002). "Extraversion" was associated with the MS score (coefficient=0.12, P=0.0003). No personality trait was significantly associated with the presence of metabolic syndrome. CONCLUSIONS: Higher "extraversion" scores were related to higher MS scores, but no personality trait was significantly associated with the presence of metabolic syndrome.