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BACKGROUND: The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR). METHODS: We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause. CONCLUSIONS: Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.
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Estudio de Asociación del Genoma Completo , Menarquia , Análisis de la Aleatorización Mendeliana , Menopausia , Metaboloma , Humanos , Menarquia/genética , Menarquia/metabolismo , Femenino , Menopausia/genética , Factores de Edad , Metabolómica/métodos , Índice de Masa CorporalRESUMEN
Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan.
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Menarquia , Análisis de la Aleatorización Mendeliana , Humanos , Femenino , Menarquia/genética , Proteómica , Biomarcadores , Menopausia/genética , Proteínas del Choque Térmico HSP40RESUMEN
Adolescent idiopathic scoliosis (AIS) is the most common form of pediatric musculoskeletal disorder. Observational studies have pointed to several risk factors for AIS, but almost no evidence exists to support their causal association with AIS. Here, we applied Mendelian randomization (MR), known to limit bias from confounding and reverse causation, to investigate causal associations between body composition and puberty-related exposures and AIS risk in Europeans and Asians. For our two-sample MR studies, we used single nucleotide polymorphisms (SNPs) associated with body mass index (BMI), waist-hip ratio, lean mass, childhood obesity, bone mineral density (BMD), 25-hydroxyvitamin D (25OHD), age at menarche, and pubertal growth in large European genome-wide association studies (GWAS), and with adult osteoporosis risk and age of menarche in Biobank Japan. We extracted estimates of the aforementioned SNPs on AIS risk from the European or Asian subsets of the largest multiancestry AIS GWAS (N = 7956 cases/88,459 controls). The results of our inverse variance-weighted (IVW) MR estimates suggest no causal association between the aforementioned risk factors and risk of AIS. Pleiotropy-sensitive MR methods yielded similar results. However, restricting our analysis to European females with AIS, we observed a causal association between estimated BMD and the risk of AIS (IVW odds ratio for AIS = 0.1, 95% confidence interval 0.01 to 0.7, p = 0.02 per SD increase in estimated BMD), but this association was no longer significant after adjusting for BMI, body fat mass, and 25OHD and remained significant after adjusting for age at menarche in multivariable MR. In conclusion, we demonstrated a protective causal effect of BMD on AIS risk in females of European ancestry, but this effect was modified by BMI, body fat mass, and 25OHD levels. Future MR studies using larger AIS GWAS are needed to investigate small effects of the aforementioned exposures on AIS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Observational studies have linked vitamin D insufficiency to pediatric type 2 diabetes (T2D), but evidence from vitamin D supplementation trials is sparse. Given the rising prevalence of pediatric T2D in all ethnicities, determining the protective role of vitamin D has significant public health importance. We tested whether serum 25-hydroxyvitamin D (25OHD) levels are causally linked to youth-onset T2D risk using Mendelian randomization (MR). We selected 54 single-nucleotide polymorphisms (SNPs) associated with 25OHD in a European genome-wide association study (GWAS) on 443,734 individuals and obtained their effects on pediatric T2D from the multi-ethnic PRODIGY GWAS (3006 cases/6061 controls). We applied inverse variance weighted (IVW) MR and a series of MR methods to control for pleiotropy. We undertook sensitivity analyses in ethnic sub-cohorts of PRODIGY, using SNPs in core vitamin D genes or ancestry-informed 25OHD SNPs. Multivariable MR accounted for the mediating effects of body mass index. We found that a standard deviation increase in 25OHD in the logarithmic scale did not affect youth-onset T2D risk (IVW MR odds ratio (OR) = 1.04, 95% CI = 0.96-1.13, p = 0.35) in the multi-ethnic analysis, and sensitivity, ancestry-specific and multivariable MR analyses showed consistent results. Our study had limited power to detect small/moderate effects of 25OHD (OR of pediatric T2D < 1.39 to 2.1). In conclusion, 25OHD levels are unlikely to have significant effects on the risk of youth-onset T2D across different ethnicities.
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Diabetes Mellitus Tipo 2 , Humanos , Adolescente , Niño , Factores de Riesgo , Análisis de la Aleatorización Mendeliana/métodos , Estudio de Asociación del Genoma Completo , Vitamina D , Calcifediol , Polimorfismo de Nucleótido SimpleRESUMEN
CONTEXT: Observational studies investigating the role of vitamin D in renal function have yielded inconsistent results. OBJECTIVE: We tested whether 25-hydroxyvitamin D (25[OH]D) serum levels are associated with renal function, and inversely, whether altered renal function causes changes in 25(OH)D, using Mendelian randomization (MR). METHODS: In this two-sample MR study, we used single nucleotide polymorphisms (SNP) associated with 25(OH)D in 443 734 Europeans and evaluated their effects on estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), chronic kidney disease (CKD) risk and progression in genome-wide association studies totaling over 1 million Europeans. To control for pleiotropy, we also used SNPs solely in DHCR7, CYP2R1, and GC, all genes with known roles in vitamin D metabolism. We performed a reverse MR, using SNPs for the above indices of renal function to study causal effects on 25(OH)D levels. RESULTS: We did not find robust evidence supporting effects of 25(OH)D on eGFR, BUN, and CKD or its progression. Our inverse variance weighted MR demonstrated a 0.56 decrease in standardized log-transformed 25(OH)D (95% CI -0.73, -0.41; P = 2.89 × 10-12) per unit increase in log-transformed eGFR. Increased BUN was associated with increased 25(OH)D (ß = 0.25, 95% CI 0.15, 0.36; P = 4.12 × 10-6 per unit increase in log-transformed BUN). Finally, genetically predicted CKD conferred a 0.05 increase in standardized log-transformed 25(OH)D level (95% CI 0.04, 0.06; P = 1.06 × 10-13). Other MR methods confirmed the findings of the main analyses. CONCLUSION: Genetically predicted CKD, increased BUN, and decreased eGFR are associated with increased 25(OH)D levels, but we found no causal effect of 25(OH)D on renal function in Europeans.
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Análisis de la Aleatorización Mendeliana , Insuficiencia Renal Crónica , Humanos , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Vitamina D , Calcifediol , Riñón/fisiología , Insuficiencia Renal Crónica/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Epidemiological studies have reported an association between amyotrophic lateral sclerosis (ALS) and different autoimmune disorders. This study aims to explore the causal relationship between autoimmune disorders and ALS using Mendelian randomization (MR). METHODS: To test the genetically predicted effects of liability towards immune-related outcomes on ALS risk, we used summary statistics from the largest European genome-wide association studies (GWAS) for these disorders in a two-sample MR setting. To do this, we extracted single nucleotide polymorphisms (SNPs) from the GWAS, which strongly associated with the 12 traits, and queried their effects in a large European ALS GWAS (27,265 cases and 110,881 controls). To avoid bias in our MR instruments related to the complex linkage disequilibrium structure of the human leukocyte antigen (HLA) region, we excluded SNPs within this region from the analyses. We computed inverse-variance weighted (IVW) MR estimates and undertook sensitivity analyses using MR methods robust to horizontal pleiotropy. We also performed a reverse MR analysis testing the causal effects of ALS on the above autoimmune traits. RESULTS: After applying Bonferroni correction for multiple testing, our MR analyses showed that the liability to autoimmune disorders does not affect ALS risk. Our reverse MR analysis also did not support the effects of liability to ALS on other autoimmune disorders. The results of the main IVW MR analyses were generally supported by our sensitivity MR analyses. The variance in the exposures explained by the sets of SNPs used as MR instruments ranged from 8.1 × 10-4 to 0.31. Our MR study was well-powered to detect effects as small as an odds ratio (OR) of 1.045 for ALS in the main MR and as small as an OR of 1.32 in the reverse MR. CONCLUSION: Our MR study does not support a relationship between liability to autoimmune disorders and ALS risk in the European population. The associations observed in epidemiological studies could be partly attributed to shared biology or environmental confounders.
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Esclerosis Amiotrófica Lateral , Enfermedades Autoinmunes , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido SimpleRESUMEN
While genome-wide association studies (GWAS) on levels of nuclear receptors are sparse, the genetics of ligands of these receptors (steroid hormones, thyroid hormones, and liposoluble vitamins) have been extensively studied in GWAS of predominantly European populations. Hundreds of genetic variants across the genome have been associated with serum levels of nuclear receptor ligands, shedding light on the physiology of hormone metabolism. These GWAS findings have been used to explore causal associations of these hormones with complex human traits and diseases in Mendelian randomization (MR) studies, and in studies using polygenic risk scores to quantify the genetic predisposition to higher/lower hormone levels. As such, besides providing insights into hormonal pathophysiology and its causal relationship with clinical complications, GWAS-identified genetic markers could ultimately play an important role in the daily clinical management of patients. As large trans-ethnic GWAS on levels of nuclear receptor ligands emerge, and with the fast advances in genotyping techniques and constant decrease of the genotyping costs, studying an individual's genetically predicted hormonal profile could be the next step in personalizing the management of patients with pathologies related to nuclear receptors and their ligands.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Marcadores Genéticos , Variación Genética , Hormonas , Humanos , Ligandos , VitaminasRESUMEN
Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit ß2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1ß (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and α1-3-N-acetylgalactosaminyltransferase and α1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets.
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Diabetes Mellitus Tipo 2 , Análisis de la Aleatorización Mendeliana , Adolescente , Adulto , Biomarcadores , Niño , Diabetes Mellitus Tipo 2/metabolismo , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Polimorfismo de Nucleótido Simple , ProteómicaRESUMEN
Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.
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Diabetes Mellitus Tipo 2 , Raquitismo , Deficiencia de Vitamina D , Anciano , Niño , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Suplementos Dietéticos , Humanos , Lactante , Raquitismo/inducido químicamente , Raquitismo/tratamiento farmacológico , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/tratamiento farmacológicoRESUMEN
OBJECTIVE: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS: We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 × 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; P = 3.7 × 10-6). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; P = 6.1 × 10-6). Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (P value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO (P value global test = 0.006). CONCLUSIONS: We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.
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Diabetes Mellitus Tipo 1 , Infecciones por Virus de Epstein-Barr , Biomarcadores , Diabetes Mellitus Tipo 1/genética , Estudio de Asociación del Genoma Completo/métodos , Herpesvirus Humano 4 , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Polimorfismo de Nucleótido SimpleRESUMEN
[This corrects the article DOI: 10.1371/journal.pmed.1003536.].
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CONTEXT: Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height. OBJECTIVE: To develop a polygenic risk score for adult height and evaluate its clinical utility. DESIGN: A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. SUBJECTS: Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature. RESULTS: Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child's parent's height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood. CONCLUSIONS: A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.
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Estatura/genética , Trastornos del Crecimiento/diagnóstico , Medición de Riesgo/métodos , Población Blanca/genética , Adulto , Anciano , Área Bajo la Curva , Niño , Preescolar , Femenino , Estudio de Asociación del Genoma Completo , Trastornos del Crecimiento/etnología , Trastornos del Crecimiento/genética , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Factores de Riesgo , Reino UnidoRESUMEN
BACKGROUND: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. OBJECTIVE: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. METHODS: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. RESULTS: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09-1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60-0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%-31.0%). CONCLUSIONS: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.
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Análisis de la Aleatorización Mendeliana , Esclerosis Múltiple , Adiponectina/genética , Índice de Masa Corporal , Estudio de Asociación del Genoma Completo , Humanos , Leptina , Análisis de Mediación , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Obesidad/epidemiología , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Vitamina DRESUMEN
BACKGROUND: Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). METHODS AND FINDINGS: For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. CONCLUSIONS: Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.
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Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Análisis de la Aleatorización Mendeliana , Deficiencia de Vitamina D/genética , Vitamina D/sangre , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 2/complicaciones , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Deficiencia de Vitamina D/sangreRESUMEN
Some commonly prescribed drugs are associated with increased risk of osteoporotic fractures. However, fracture risk stratification using skeletal measures is not often performed to identify those at risk before these medications are prescribed. We tested whether a genomically predicted skeletal measure, speed of sound (gSOS) from heel ultrasound, which was developed in 341,449 individuals from UK Biobank and tested in a separate subset consisting of 80,027 individuals, is an independent risk factor for fracture in users of fracture-related drugs (FRDs). To do this, we first assessed 80,014 UK Biobank participants (including 12,678 FRD users) for incident major osteoporotic fracture (MOF, n = 1189) and incident hip fracture (n = 209). Effects of gSOS on incident fracture were adjusted for baseline clinical fracture risk factors. We found that each standard deviation decrease in gSOS increased the adjusted odds of MOF by 42% (95% confidence interval [CI] 1.34-1.51, p < 2 × 10-16 ) and of hip fracture by 31% (95% CI 1.15-1.50, p = 9 × 10-5 ). gSOS below versus above the mean increased the adjusted odds of MOF by 79% (95% CI 1.58-2.01, p < 2 × 10-16 ) and of hip fracture by 42% (95% CI 1.08-1.88, p = 1.3 × 10-2 ). Among FRD users, each standard deviation decrease in gSOS increased the adjusted odds of MOF by 29% (nMOF = 256, 95% CI 1.14-1.46, p = 7 × 10-5 ) and of hip fracture by 30% (nhip fracture = 68, 95% CI 1.02-1.65, p = 0.0335). FRD users with gSOS below versus above the mean had a 54% increased adjusted odds of MOF (95% 1.19-1.99, p = 8.95 × 10-4 ) and a twofold increased adjusted odds of hip fracture (95% 1.19-3.31, p = 8.5 × 10-3 ). We therefore showed that genomically predicted heel SOS is independently associated with incident fracture among FRD users. © 2020 American Society for Bone and Mineral Research.
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Densidad Ósea , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Fracturas de Cadera , Fracturas Osteoporóticas , Fracturas de Cadera/inducido químicamente , Fracturas de Cadera/epidemiología , Fracturas de Cadera/genética , Humanos , Fracturas Osteoporóticas/inducido químicamente , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/genética , Preparaciones Farmacéuticas , Medición de Riesgo , Factores de Riesgo , UltrasonografíaRESUMEN
BACKGROUND/OBJECTIVES: Physical activity is beneficial to lipid profiles; however, the association between sedentary behavior and sleep and pediatric dyslipidemia remains unclear. We aimed to investigate whether sedentary behavior or sleep predicted lipid profiles in children over a 2-year period. SUBJECTS/METHODS: Six hundered and thirty children from the QUALITY cohort, with at least one obese parent, were assessed prospectively at ages 8-10 and 10-12 years. Measures of sedentary behavior included self-reported TV viewing and computer/video game use. Seven-day accelerometry was used to derive sedentary behavior and sleep duration. Adiposity was assessed using DEXA scans. Twenty-four-hour dietary recalls yielded estimates of carbohydrate and fat intake. Outcomes included fasting total cholesterol, triglycerides, HDL and LDL-cholesterol. Multivariable models were adjusted for adiposity and diet. RESULTS: At both Visit 1 (median age 9.6 year) and Visit 2 (median age 11.6 year), children were of normal weight (55%), overweight (22%), or obese (22%). Every additional hour of TV viewing at Visit 1 was associated with a 7.0% triglyceride increase (95% CI: 3.5, 10.6; P < 0.01) and 2.6% HDL decrease (95% CI: -4.2, -0.9; P < 0.01) at Visit 2; findings remained significant after adjusting for adiposity and diet. Every additional hour of sleep at Visit 1 predicted a 4.8% LDL decrease (95% CI: -9.0, -0.5; P = 0.03) at Visit 2, after adjusting for fat intake; this association became nonsignificant once controlling for adiposity. CONCLUSIONS: Longer screen time during childhood appears to deteriorate lipid profiles in early adolescence, even after accounting for other major lifestyle habits. There is preliminary evidence of a deleterious effect of shorter sleep duration, which should be considered in further studies.
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Lípidos/sangre , Tiempo de Pantalla , Sueño/fisiología , Acelerometría , Niño , Ejercicio Físico/fisiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Sobrepeso/epidemiología , Obesidad Infantil/epidemiología , Conducta Sedentaria , TelevisiónRESUMEN
We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.