We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a 2 = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c 2 = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a 2 = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a 2 = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c 2 = 0.31; 0.29-0.33 and c 2 = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.
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 ¼ 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 ¼ 2507, mean age ¼ 44.4 years, men ¼ 44.3%) showed that BMI but not aWC was positively associated with bone mineral density (BMD for weight-bearing bones: 0.063 AE 0.016 g/cm 2 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 AE 0.011 g/cm 2 ), 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. Fig. 3. MR-Egger regression plots for BMI and BMD in weight-bearing (A) and non-weight-bearing bones (B). Results from MR-Egger regression analysis to assess horizontal pleiotropy are presented. Blue line represents the MR-Egger regression estimate for the association between BMI and BMD in weightbearing (A) and non-weight-bearing bones (B). For both sites, the y-intercept estimates were not significantly different from zero (weight-bearing bones: ¼ 0.001, p ¼ 0.55; non-weight-bearing bones: ¼ -0.004, p ¼ 0.67), suggesting that there is no horizontal pleiotropy.
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.
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.
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.
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.
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