Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study.

BACKGROUND: Previous observational studies reported that a lower serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with a higher burden of cerebral small vessel disease (cSVD). The causality of this association is uncertain, but it would be clinically important, given that 25(OH)D can be a target for intervention. We tried to examine the causal effect of 25(OH)D concentration on cSVD-related phenotypes using a Mendelian randomization approach. METHODS: Genetic instruments for each serum 25(OH)D concentration and cSVD-related phenotypes (lacunar stroke, white matter hyperintensity, cerebral microbleeds, and perivascular spaces) were derived from large-scale genome-wide association studies. We performed 2-sample Mendelian randomization analyses with multiple post hoc sensitivity analyses. A bidirectional Mendelian randomization approach was also used to explore the possibility of reverse causation. RESULTS: We failed to find any significant causal effect of 25(OH)D concentration on cSVD-related phenotypes (odds ratio [95% CI], 1.00 [0.87-1.16], 1.01 [0.96-1.07], 1.06 [0.85-1.33], 1.00 [0.97-1.03], 1.02 [0.99-1.04], 1.01 [0.99-1.04] for lacunar stroke, white matter hyperintensity, cerebral microbleeds, and white matter, basal ganglia, hippocampal perivascular spaces, respectively). These results were reproduced in the sensitivity analyses accounting for genetic pleiotropy. Conversely, when we examined the effects of cSVD phenotypes on 25(OH)D concentration, cerebral microbleeds were negatively associated with 25(OH)D concentration (0.94 [0.92-0.96]). CONCLUSIONS: Given the adequate statistical power (>0.8) of the analyses, our findings suggest that the previously reported association between 25(OH)D concentration and cSVD phenotypes might not be causal and partly attributed to reverse causation.

Exploring the causal inference of migraine on stroke: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Previous observational studies have reported that patients with migraine have an increased risk of stroke. We explored whether migraine has a causal effect on stroke using a two-sample Mendelian randomization approach. METHODS: Genetic instruments were selected from large genome-wide association studies of migraine and stroke. A two-sample Mendelian randomization analysis was performed, along with sensitivity analysis. We used migraine subtypes (any migraine, migraine with aura, migraine without aura) as risk factors and stroke, ischemic stroke, and hemorrhagic stroke as outcomes for this analysis. Ischemic stroke subtypes were also included to explore the underlying pathogenesis linking migraine to stroke. RESULTS: Migraine did not show any association with stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.87-1.03), ischemic stroke (OR, 0.93; 95% CI, 0.85-1.02), or hemorrhagic stroke (OR, 1.26; 95% CI, 0.84-1.91), suggesting that the observed association may not be causal. Neither migraine with aura nor without aura showed causal relationship with outcomes. The sensitivity analysis supported the results of the primary analysis. Regarding ischemic stroke subtypes, migraine seemed to have a negative association with large-artery atherosclerosis (OR, 0.81; 95% CI, 0.68-0.95), whereas associations with small-vessel occlusion or cardioembolism were not evident. CONCLUSIONS: Contrary to previous observational studies, we were unable to find any causal relationship between migraine and stroke. However, the suggested negative association of migraine in large-artery atherosclerosis warrants further research.

Heritability of Cardiothoracic Ratio and Aortic Arch Calcification in Twins.

Background and Objectives: Aortic arch calcification (AoAC) is associated with a variety of cardiovascular complications. The measurement and grading of AoAC using posteroanterior (PA) chest X-rays are well established. The cardiothoracic ratio (CTR) can be simultaneously measured with PA chest X-rays and used as an index of cardiomegaly. The genetic and environmental contributions to the degree of the AoAC and CTR are not well understood. The purpose of this study was to investigate the effect of genetics and environmental factors on the AoAC and CTR. Materials and Methods: A total of 684 twins from the South Korean twin registry (261 monozygotic, MZ and 81 dizygotic, DZ pairs; mean age 38.6 ± 7.9 years, male/female = 264/420) underwent PA chest X-rays. Cardiovascular risk factors and anthropometric data were also collected. The AoAC and CTR were measured and graded using a standardized method. A structural equation method was used to calculate the proportion of variance explained by genetic and environmental factors behind AoAC and CTR. Results: The within-pair differences were low regarding the grade of AoAC, with only a few twin pairs showing large intra-pair differences. We found that the thoracic width showed high heritability (0.67, 95% CI: 0.59-0.73, p = 1). Moderate heritability was detected regarding cardiac width (0.54, 95% CI: 0.45-0.62, p = 0.572) and CTR (0.54, 95% CI: 0.44-0.62, p = 0.701). Conclusions: The heritable component was significant regarding thoracic width, cardiac width, and the CTR.

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians.

Genetic studies of plasma TG levels have identified associations with multiple candidate loci on chromosome11q23.3, which harbors a number of genes, including BUD13, ZNF259, and APOA5-A4-C3-A1. This study aimed to examine whether these multiple candidate genes on the 11q23.3 regions exert independent effects on TG levels or whether their effects are confounded by linkage disequilibrium (LD). We performed a genome-wide association study and consequent fine-mapping analyses on TG levels in two Korean population-based cohorts: the Korea Association Resource study (n = 8,223) and the Healthy Twin study (n = 1,735). A total of 301 loci reached genome-wide significance level in pooled analysis, including 10 SNPs with weak LD (r(2) < 0.06) clustered on 11q23.3: ApoA5 (rs651821, rs2075291); ZNF259 (rs964184, rs603446); BUD13 (rs11216126); Apoa4 (rs7396851); SIK3 (rs12292858); PCSK7 (rs199890178); PAFAH1B2 (rs12420127), and SIDT2 (rs2269399). When the inter-dependence between alleles was examined using conditional models, five loci on BUD13, ZNF259, and ApoA5 showed possible independent associations. A haplotype analysis using five SNPs revealed both hyper- and hypotriglyceridemic haplotypes, which are relatively common in Koreans (haplotype frequency 0.08-0.22). Our findings suggest the presence of multiple functional loci on 11q23.3, which might exert their effects on plasma TG level independently or through complex interactions between functional loci.

Assessment of aortic valve area on cardiac computed tomography in symptomatic bicuspid aortic stenosis: Utility and differences from Doppler echocardiography.

Background: In this study, we investigate the utility of geometric orifice area (GOA) on cardiac computed tomography (CT) and differences from effective orifice area (EOA) on Doppler echocardiography in patients with bicuspid aortic stenosis (AS). Methods: A total of 163 patients (age 64 ± 10 years, 56.4% men) with symptomatic bicuspid AS who were referred for surgery and underwent both cardiac CT and echocardiography within 3 months were studied. To calculate the aortic valve area, GOACT was measured by multiplanar CT planimetry, and EOAEcho was calculated by the continuity equation with Doppler echocardiography. The relationships between GOACT and EOAEcho and patient symptom scale, biomarkers, and left ventricular (LV) functional variables were analyzed. Results: There was a significant but modest correlation between EOAEcho and GOACT (r = 0.604, p < 0.001). Both EOAEcho and GOACT revealed significant correlations with mean pressure gradient and peak transaortic velocity, and the coefficients were higher in EOAEcho than in GOACT. EOAEcho of 1.05 cm2 and GOACT of 1.25 cm2 corresponds to hemodynamic cutoff values for diagnosing severe AS. EOAEcho was well correlated with the patient symptom scale and log NT-pro BNP, but GOACT was not. In addition, EOAEcho had a higher correlation coefficient with estimated LV filling pressure and LV global longitudinal strain than GOACT. Conclusion: GOACT can be used to evaluate the severity of bicuspid AS. The threshold for GOACT for diagnosing severe AS should be higher than that for EOAEcho. However, EOAEcho is still the method of choice because EOAEcho showed better correlations with clinical and functional variables than GOACT.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Causal relationship between the timing of menarche and young adult body mass index with consideration to a trend of consistently decreasing age at menarche.

Younger age at menarche (AAM) is associated with higher body mass index (BMI) for young women. Considering that continuous trends in decreasing AAM and increasing BMI are found in many countries, we attempted to assess whether the observed negative association between AAM and young adult BMI is causal. We included 4,093 women from the Korean Genome and Epidemiology Study (KoGES) and Healthy twin Study (HTS) with relevant epidemiologic data and genome-wide marker information. To mitigate the remarkable differences in AAM across generations, we converted the AAM to a generation-standardized AAM (gsAAM). To test causality, we applied the Mendelian randomization (MR) approach, using a genetic risk score (GRS) based on 14 AAM-associated single nucleotide polymorphisms (SNPs). We constructed MR models adjusting for education level and validated the results using the inverse-variance weighted (IVW), weighted median (WM), MR-pleiotropy residual sum and outliers test (MR-PRESSO), and MR-Egger regression methods. We found a null association using observed AAM and BMI level (conventional regression; -0.05 [95% CIs -0.10-0.00] per 1-year higher AAM). This null association was replicated when gsAAM was applied instead of AAM. Using the two-stage least squares (2SLS) approach employing a univariate GRS, the association was also negated for both AAM and gsAAM, regardless of model specifications. All the MR diagnostics suggested statistically insignificant associations, but weakly negative trends, without evidence of confounding from pleiotropy. We did not observe a causal association between AAM and young adult BMI whether we considered the birth cohort effect or not. Our study alone does not exclude the possibility of existing a weak negative association, considering the modest power of our study design.

Author Correction: An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Obesity and Bone Health Revisited: A Mendelian Randomization Study for Koreans.

Epidemiologic studies have replicated positive associations between obesity and bone health, but their mechanisms are still debatable. We aimed to scrutinize an association between bone health and obesity using genetic instrumental variables (IVs) with the distinction of general versus abdominal obesity. We selected independent IVs of body mass index (BMI) and BMI-adjusted waist circumference (aWC, a proxy of a central fat distribution) by combining novel genomewide searches from the Korean Genome Epidemiology Study (KoGES) consortium and existing reports. We evaluated the associations of obesity indices with bone health measures for weight-bearing and non-weight-bearing bones, applying standard Mendelian randomization analyses. The IVs for BMI and aWC selected from KoGES cohort studies (n = 14,389) explained its own trait only, negating the mutual correlation at the phenotypic level. Two-stage least squares analyses using an independent cohort study (n = 2507, mean age = 44.4 years, men = 44.3%) showed that BMI but not aWC was positively associated with bone mineral density (BMD for weight-bearing bones: 0.063 ± 0.016 g/cm2 per one standard deviation increase in BMI), implying the fat distribution might be neutral. The association was weaker for non-weight-bearing bones (BMI on BMD: 0.034 ± 0.011 g/cm2 ), and for postmenopausal women the association was absent. Obesity increased both bone area and bone mineral content (BMC) to a lesser degree, but the increase in BMC was not evident for menopausal women. When we stratified the weight into lean body mass and fat mass, the increase in BMD was more evident for lean body mass, and fat mass showed a beneficial role only for men and premenopausal women. Our findings suggest that bone health might gain little from obesity, if any, through its added weight, and other means to prevent bone loss would be essential for postmenopausal women. © 2019 American Society for Bone and Mineral Research.

An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer.

Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea. However, rare and low-frequency variants have a significant influence on the heritability of the disease. The contributions of rare variants to prostate cancer susceptibility have not yet been systematically evaluated in a Korean population. In this work, we present a large-scale exome-wide rare variant analysis of 7,258 individuals (985 cases with prostate cancer and 6,273 controls). In total, 19 rare variant loci spanning 7 genes contributed to an association with prostate cancer susceptibility. In addition to replicating previously known susceptibility genes (e.g., CDYL2, MST1R, GPER1, and PARD3B), 3 novel genes were identified (FDR q < 0.05), including the non-coding RNAs ENTPD3-AS1, LOC102724438, and protein-coding gene SPATA3. Additionally, 6 pathways were identified based on identified variants and genes, including estrogen signaling pathway, signaling by MST1, IL-15 production, MSP-RON signaling pathway, and IL-12 signaling and production in macrophages, which are known to be associated with prostate cancer. In summary, we report novel genes and rare variants that potentially play a role in prostate cancer susceptibility in the Korean population. These observations demonstrated a path towards one of the fundamental goals of precision medicine, which is to identify biomarkers for a subset of the population with a greater risk of disease than others.

Reliability and Validity of the Beck Depression Inventory-II among Korean Adolescents.

OBJECTIVE: The Beck Depression Inventory-II (BDI-II) is one of the most popular scales for evaluating the severity of depression in adolescents as well as adults. The prevalence of depression increases during adolescence, and it has shown a rapid increase with occurrence at an earlier age and a tendency to continue into adulthood. Data from an adolescent nonclinical sample provides us more information related to depressive symptoms as potential risk factors. The current study was designed to two objectives: 1) to analyze the reliability and validity the BDI-II among Korean adolescents and 2) to evaluate the factorial structure in a Korean nonclinical adolescent sample. METHODS: The participants included 1072 adolescent boys and girls. We assessed the internal consistency, corrected item-total correlation, and the convergent validity of the BDI-II. We also performed confirmatory factor analyses to determine the internal structure of the BDI-II for Korean adolescents using Mplus 6.1. RESULTS: The Cronbach's alpha for the BDI-II total score was 0.89. The correlation between the BDI-II and the PHQ-9 was strong (r=0.75), and anxiety-related measures were 0.68 and 0.71, which were also in the high range. Among the five different factor structures, the modified three-factor model demonstrated the best overall fit. CONCLUSION: The BDI-II is a reliable tool for measuring the severity of depressive symptoms in Korean adolescents. Therefore, the findings can provide basic information for examining the prevalence rate, intervention strategies for depression in adolescents.

Exome-based genome-wide association study and risk assessment using genetic risk score to prostate cancer in the Korean population.

PURPOSE: To investigate exome-wide genetic variants associated with prostate cancer (PCa) in Koreans and evaluate the discriminative ability by the genetic risk score (GRS). PATIENTS AND METHODS: We prospectively recruited 1,001 PCa cases from a tertiary hospital and conducted a case-control study including 2,641 healthy men (Stage I). Participants were analyzed using HumanExome BeadChip. For the external validation, additionally enrolled 514 PCa cases and 548 controls (independent cohort) were analyzed for the identified single nucleotide polymorphisms (SNPs) of Stage I (Stage II). The GRS was calculated as a non-weighted sum of the risk allele counts and investigated for accuracy of prediction of PCa. RESULTS: the mean age was 66.3 years, and the median level of prostate specific antigen (PSA) was 9.19 ng/ml in PCa cases. In Stage I, 4 loci containing 5 variants (rs1512268 on 8p21.2; rs1016343 and rs7837688 on 8q24.21; rs7501939 on 17q12, and rs2735839 on 19q13.33) were confirmed to reach exome-wide significance (p<8.3x10-7). In Stage II, the mean GRS was 4.23 ± 1.44 for the controls and 4.78 ± 1.43 for the cases. As a reference to GRS 4, GRS 6, 7 and 8 showed a statistically significant risk of PCa (OR=1.85, 2.11 and 3.34, respectively). CONCLUSIONS: The five variants were validated to associate with PCa in firstly performed exome-wide study in Koreans. The addition of individualized calculated GRS effectively enhanced the accuracy of prediction. These results need to be validated in future studies.

Quantitative EEG and medial temporal lobe atrophy in Alzheimer's dementia: Preliminary study.

BACKGROUNDS: The electroencephalogram (EEG) abnormalities in Alzheimer's disease (AD) have been widely reported, and medial temporal lobe atrophy (MTLA) is one of the hallmarks in early stage of AD. We aimed to assess the relationship between EEG abnormalities and MTLA and its clinical validity. MATERIALS AND METHODS: A total of 18 patients with AD were recruited (the mean age: 77.83 years). Baseline EEGs were analyzed with quantitative spectral analysis. MTLA was assessed by a T1-axial visual rating scale (VRS). RESULTS: In relative power spectrum analysis according to the right MTLA severity, the power of theta waves in C4, T4, F4, F8, and T5 increased significantly and the power of beta waves in T6, C4, T4, F8, T5, P3, T3, and F7 decreased significantly in severe atrophy group. In relative power spectrum analysis according to the left MTLA severity, the power of theta waves in T3 increased significantly and that of beta waves in P4, T6, C4, F4, F8, T5, P3, C3, T3, F3, and F7 decreased significantly in severe atrophy group. CONCLUSION: The severe MTLA group, regardless of laterality, showed more severe quantitative EEG alterations. These results suggest that quantitative EEG abnormalities are correlated with the MTLA, which may play an important role in AD process.