Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease.

Background: Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

Metabolically favorable adiposity and bone mineral density: a Mendelian randomization analysis.

OBJECTIVE: This analysis assessed the putative causal association between genetically predicted percent body fat and areal bone mineral density (aBMD) and, more specifically, the association between genetically predicted metabolically "favorable adiposity" (MFA) and aBMD at clinically relevant bone sites. METHODS: Mendelian randomization was used to assess the relationship of MFA and percent body fat with whole-body, lumbar spine, femoral neck, and forearm aBMD. Sex-stratified and age-stratified exploratory analyses were conducted. RESULTS: In all MR analyses, genetically predicted MFA was inversely associated with aBMD for the whole body (ß = -0.053, p = 0.0002), lumbar spine (ß = -0.075; p = 0.0001), femoral neck (ß = -0.045; p = 0.008), and forearm (ß = -0.115; p = 0.001). This negative relationship was strongest in older individuals and did not differ by sex. The relationship between genetically predicted percent body fat and aBMD was nonsignificant across all Mendelian randomization analyses. Several loci that were associated at a genome-wide significance level (p < 5 × 10-8 ) in opposite directions with body fat and aBMD measures were also identified. CONCLUSIONS: This study did not support the hypothesis that MFA protects against low aBMD. Instead, it showed that MFA may result in lower aBMD. Further research is needed to understand how MFA affects aBMD and other components of bone health such as bone turnover, bone architecture, and osteoporotic fractures.

Visceral adipose tissue and cardiometabolic risk factors in young Hispanic and non-Hispanic girls.

Background: Risk factors for cardiometabolic diseases (e.g., type 2 diabetes, cardiovascular disease) can begin developing in childhood. Elevated body mass index (BMI) is associated with greater likelihood of developing such diseases; however, this relationship varies by race and ethnicity. Notably, Hispanics tend to have high rates of obesity and are disproportionately affected by type 2 diabetes. We aimed to determine if visceral adiposes tissue (VAT) is associated with cardiometabolic risk factors (i.e., triglycerides, cholesterol, insulin resistance, C-reactive protein, and blood pressure), independent of BMI percentile, in a sample of primarily Hispanic adolescent girls. Methods and results: A total of 337 girls (73% Hispanic) took part in the cross-sectional study. Hispanic girls generally had greater BMI percentile, VAT, and cardiometabolic risk factors compared to non-Hispanic girls. Multiple linear regression was used to assess the relationships between Dual-energy X-ray Absorptiometry (DXA)-derived VAT and cardiometabolic outcomes, controlling for BMI percentile (<85th percentile or ≥85th percentile), age, ethnicity (Hispanic/non-Hispanic), and Tanner stage. Significant interactions between VAT and BMI percentile were identified for almost all cardiometabolic outcomes. Upon stratification, the association between VAT and cardiometabolic outcomes was strongest in girls ≥85th BMI percentile, as compared to girls <85th percentile. However, VAT was only significantly associated with higher triglycerides (girls ≥85th percentile) and higher insulin resistance (both BMI percentiles) after stratification. Conclusion: VAT was associated with increased triglycerides and insulin resistance in girls with overweight or obesity. These findings warrant further investigation between VAT and cardiometabolic health in Hispanic adolescents who tend to accumulate more adipose tissue during adolescence.

Genome-wide Association Study of Liking for Several Types of Physical Activity in the UK Biobank and Two Replication Cohorts.

INTRODUCTION: A lack of physical activity (PA) is one of the most pressing health issues today. Our individual propensity for PA is influenced by genetic factors. Stated liking of different PA types may help capture additional and informative dimensions of PA behavior genetics. METHODS: In over 157,000 individuals from the UK Biobank, we performed genome-wide association studies of five items assessing the liking of different PA types, plus an additional derived trait of overall PA-liking. We attempted to replicate significant associations in the Netherlands Twin Register (NTR) and TwinsUK. Additionally, polygenic scores (PGS) were trained in the UK Biobank for each PA-liking item and for self-reported PA behavior, and tested for association with PA in the NTR. RESULTS: We identified a total of 19 unique significant loci across all five PA-liking items and the overall PA-liking trait, and these showed strong directional consistency in the replication cohorts. Four of these loci were previously identified for PA behavior, including CADM2 , which was associated with three PA-liking items. The PA-liking items were genetically correlated with self-reported ( rg = 0.38-0.80) and accelerometer ( rg = 0.26-0.49) PA measures, and with a wide range of health-related traits. Each PA-liking PGS significantly predicted the same PA-liking item in NTR. The PGS of liking for going to the gym predicted PA behavior in the NTR ( r2 = 0.40%) nearly as well as a PGS based on self-reported PA behavior ( r2 = 0.42%). Combining the two PGS into a single model increased the r2 to 0.59%, suggesting that PA-liking captures distinct and relevant dimensions of PA behavior. CONCLUSIONS: We have identified the first loci associated with PA-liking and extended our understanding of the genetic basis of PA behavior.

Identification of genetic loci simultaneously associated with multiple cardiometabolic traits.

BACKGROUND AND AIMS: Cardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits. METHODS AND RESULTS: We conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high- density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N = 356,574-456,823). Multiple loci reached genome-wide levels of significance (N = 145-333) for each trait, but only four loci (in/near VEGFA, GRB14-COBLL1, KLF14, and RGS19-OPRL1) were associated with risk across all seven traits (P < 5 × 10-8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses. GRB14-COBLL1 showed the most consistent replication, revealing nominally significant associations (P < 0.05) with all traits except DBP. CONCLUSIONS: Our analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.

MRI Based Validation of Abdominal Adipose Tissue Measurements From DXA in Postmenopausal Women.

INTRODUCTION: Visceral adipose tissue (VAT) is a hypothesized driver of chronic disease. Dual-energy X-ray absorptiometry (DXA) potentially offers a lower cost and more available alternative compared to gold-standard magnetic resonance imaging (MRI) for quantification of abdominal fat sub-compartments, VAT and subcutaneous adipose tissue (SAT). We sought to validate VAT and SAT area (cm2) from historical DXA scans against MRI. METHODOLOGY: Participants (n = 69) from the Women's Health Initiative (WHI) completed a 3 T MRI scan and a whole body DXA scan (Hologic QDR2000 or QDR4500; 2004-2005). A subset of 43 participants were scanned on both DXA devices. DXA-derived VAT and SAT at the 4th lumbar vertebrae (5 cm wide) were analyzed using APEX software (v4.0, Hologic, Inc., Marlborough, MA). MRI VAT and SAT areas for the corresponding DXA region of interest were quantified using sliceOmatic software (v5.0, Tomovision, Magog, Canada). Pearson correlations between MRI and DXA-derived VAT and SAT were computed, and a Bland-Altman analysis was performed. RESULTS: Participants were primarily non-Hispanic white (86%) with a mean age of 70.51 ± 5.79 years and a mean BMI of 27.33 ± 5.40 kg/m2. Correlations between MRI and DXA measured VAT and SAT were 0.90 and 0.92, respectively (p ≤ 0.001). Bland-Altman plots showed that DXA-VAT slightly overestimated VAT on the QDR4500 (-3.31 cm2); this bias was greater in the smaller subset measured on the older DXA model (QDR2000; -30.71 cm2). The overestimation of DXA-SAT was large (-85.16 to -118.66 cm2), but differences were relatively uniform for the QDR4500. CONCLUSIONS: New software applied to historic Hologic DXA scans provide estimates of VAT and SAT that are well-correlated with criterion MRI among postmenopausal women.

Assessing Interactions between PNPLA3 and Dietary Intake on Liver Steatosis in Mexican-Origin Adults.

Mexican-origin (MO) adults have among the highest rates of nonalcoholic fatty liver disease (NAFLD) placing them at increased risk of liver cancer. Evidence suggests that a single nucleotide polymorphism (SNP) in the PNPLA3 gene, rs738409, increases the risk and progression of NAFLD and may modify the relationship between certain dietary factors and liver steatosis. The purpose of this study was to identify whether interactions exist between specific dietary factors and rs738409 genotype status among MO adults in relation to levels of liver steatosis. We analyzed cross-sectional data from a sample of 288 MO adults. Participants completed at least two 24-h dietary recalls. Multiple linear regression was performed assuming an additive genetic model to test the main effects of several dietary variables on levels of hepatic steatosis, adjusting for covariates. To test for effect modification, the product of the genotype and the dietary variable was included as a covariate in the model. No significant association between dietary intake and level of hepatic steatosis was observed, nor any significant gene-diet interactions. Our findings suggest that dietary intake may have the same magnitude of protective or deleterious effect even among MO adults with high genetic risk for NAFLD and NAFLD progression.

Influence of Changes in Soft Tissue Composition on Changes in Bone Strength in Peripubertal Girls: The STAR Longitudinal Study.

Obesity and osteoporosis remain two major public health concerns. Soft tissue composition and bone are interrelated; however, it is still not well understood how changes in adiposity during adolescence affect bone development. The aim of this study was to assess how changes in DXA-derived total body lean mass (TBLM) and total body fat mass (TBFM) associate with 2-year changes in bone outcomes at the 20% femur, 66% tibia, 66% radius, and 4% tibia, as measured by pQCT, during the years surrounding the onset of menarche in a cohort of 9- to 12-year-old (baseline) adolescent girls (70% Hispanic). From baseline to 2-year follow-up, girls showed statistically significant increases in all bone outcomes, except radial endosteal circumference. In separate linear regression models, change in TBLM and change in TBFM were both positively associated with 2-year changes in bone outcomes at all measured bone sites, after controlling for relevant covariates. However, when change in TBLM and change in TBFM were included in the same model, change in TBLM was the predominant predictor of bone outcomes, explaining 4% to 14% of the variance in bone strength outcomes. Change in TBFM remained a positive predictor of tibia polar strength strain index (SSIp) (2% variance explained). A significant interaction between change in TBFM and menarcheal status was identified at the radius for SSIp and indicated that greater gains in TBFM were beneficial for SSIp in girls that were premenarcheal at baseline but detrimental for girls who were postmenarcheal at baseline. The overall findings suggest that changes in TBLM during the peripubertal years have a greater influence on bone outcomes than changes in TBFM. While gains in TBFM might benefit the weight bearing 66% tibia, greater gains in TBFM may be detrimental to bone development at the non-weight bearing 66% radius after the onset of menarche. © 2020 American Society for Bone and Mineral Research (ASBMR).

Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood.

One-carbon metabolism is essential for multiple cellular processes and can be assessed by the concentration of folate metabolites in the blood. One-carbon metabolites serve as methyl donors that are required for epigenetic regulation. Deficiencies in these metabolites are associated with a variety of poor health outcomes, including adverse pregnancy complications. DNA methylation is known to vary with one-carbon metabolite concentration, and therefore may modulate the risk of adverse pregnancy outcomes. This study addresses changes in one-carbon indices over pregnancy and the relationship between maternal and child DNA methylation and metabolite concentrations by leveraging data from 24 mother-infant dyads. Five of the 13 metabolites measured from maternal blood and methylation levels of 993 CpG sites changed over the course of pregnancy. In dyads, maternal and fetal one-carbon concentrations were highly correlated, both early in pregnancy and at delivery. The 993 CpG sites whose methylation levels changed over pregnancy in maternal blood were also investigated for associations with metabolite concentrations in infant blood at delivery, where five CpG sites were associated with the concentration of at least one metabolite. Identification of CpG sites that change over pregnancy may result in better characterization of genes and pathways involved in maintaining a healthy, term pregnancy.