Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m2, P = 1.9 × 10−105), and all participants (0.30 [0.30, 0.35] kg/m2, P = 3.6 × 10−107). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10−16), and relative weak associations with lower total energy intake (−6.4 [−10.1, −2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (−0.07 [−0.11, −0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10−9) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposit

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course

Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus

To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1×10-11 observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ±500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6×10-31 and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42×10-10) for rs4609139 and mapping to C7orf58. We a

Maternal fish consumption, fetal growth and the risks of neonatal complications: The Generation R Study

Maternal fish consumption during pregnancy has been suggested to affect birth outcomes. Previous studies mainly focused on birth outcomes and did not study fetal growth during pregnancy. In a prospective cohort study from early pregnancy onwards in The Netherlands, we assessed the associations of first-trimester maternal total-fish, lean-fish, fatty-fish and shellfish consumption with fetal growth characteristics in the second and third trimesters, growth characteristics at birth and the risks of neonatal complications, including pre-term birth, low birth weight and small for gestational age. In total, 3380 mothers completed a 293-item semi-quantitative FFQ to obtain information about fish consumption during the first trimester of pregnancy. Head circumference, femur length and fetal weight were estimated in the second and third trimesters by ultrasound. Information about birth anthropometrics and neonatal complications was available from hospital and midwife registries. Maternal older age, higher educational level, folic acid supplement use, alcohol use and not smoking were associated with higher fish consumption (P < 0.01). After adjustment, we observed no consistent associations of maternal total-fish consumption or specific consumption of lean fish, fatty fish or shellfish with fetal growth characteristics in the second and third trimesters and at birth. Likewise, total-fish consumption or specific consumption of any type of fish was not consistently associated with the risks of neonatal complications. These findings suggest that in a population with a relatively low fish intake, consumption of lean fish, fatty fish or shellfish in the first trimester is not associated with fetal growth or the risks of neonatal complications

Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus

To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1×10-11 observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ±500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6×10-31 and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42×10-10) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9×10-16) and rs7801723 (P = 8.9×10-28), also mapping to C7orf58 (r2 = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life