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

Abstract

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.

The bone-sparing effects of estrogen and WNT16 are independent of each other

“…In the brain, estrogen signaling activates WNT by down-regulating dickkopf-1 (Dkk1), a WNT antagonist, to prevent neurodegeneration (27). In the uterus, estrogen prompts the canonical WNT signaling pathway in the uterine epithelium to induce uterine epithelial cell growth (28), and in breast cancer, ERα activation enhances cell growth via WNT signaling (29).Human genetic studies followed by subsequent mechanistic studies have recently revealed that WNT16 is a key physiological regulator of cortical bone mass and nonvertebral fracture risk (4,5,(30)(31)(32)(33). We recently demonstrated that WNT16 is osteoblast-derived and inhibits osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts (3).…”

“…Human genetic studies followed by subsequent mechanistic studies have recently revealed that WNT16 is a key physiological regulator of cortical bone mass and nonvertebral fracture risk (4,5,(30)(31)(32)(33). We recently demonstrated that WNT16 is osteoblast-derived and inhibits osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts (3).…”

THRA and DIO2 mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women

“…These studies did not identify any relationships between variation in bone parameters and genetic variation across the THRA locus. Furthermore, osteoporosis genome-wide association (GWA) studies have not identified associations between THRA or DIO2 and BMD or fracture (27,28,29,30). This is not surprising because GWA studies investigate common variation among very large numbers of SNPs across the entire genome to identify genetic associations with quantitative traits (31), and they are not designed to detect rare sequence variants or causative mutations for single gene disorders (32).…”

Multifactorial Pathogenesis of Osteoporosis and the Role of Genes of Canonical WNT-Signaling Pathway

“…Мета-анализ Medina-Gomez c. и соавт. [19] показал на моделях у животных, при обследовании детей (n=2660) и пременопа-узальных женщин (n=1014) существенное влияние SNPs в локусе гена WNT16 (rs917727 и др.) на формирование общей массы костной ткани.…”