An adhesion G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

Liu, Zhaoyang; Hussien, Amro A.; Wang, Yunjia; Heckmann, Terry; González, R. Gilberto; Karner, Courtney M.; Snedeker, Jess G.; Gray, Ryan S.

doi:10.7554/elife.67781

Cited by 19 publications

(17 citation statements)

References 81 publications

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“…Similarly, a common variant (rs1891308) near ADGRG6 , a G protein-coupled receptor, is associated with increased torso length. Mice with conditional knockouts in ADGRG6 have spine abnormalities and spine alignments directly correlated with reduced torso length ( 52 ). Thus, GWAS of skeletal proportions pinpoints genes previously associated with skeletal developmental biology and Mendelian skeletal phenotypes and identifies candidates for future functional and knockout studies.…”

Section: Resultsmentioning

confidence: 99%

The genetic architecture of the human skeletal form

Kun

Javan

Smith

et al. 2023

Preprint

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The human skeletal form underlies our ability to walk on two legs, but unlike standing height, the genetic basis of limb lengths and skeletal proportions is less well understood. Here we applied a deep learning model to 31,221 whole body dual-energy X-ray absorptiometry (DXA) images from the UK Biobank (UKB) to extract 23 different image-derived phenotypes (IDPs) that include all long bone lengths as well as hip and shoulder width, which we analyzed while controlling for height. All skeletal proportions are highly heritable (~40-50%), and genome-wide association studies (GWAS) of these traits identified 179 independent loci, of which 102 loci were not associated with height. These loci are enriched in genes regulating skeletal development as well as associated with rare human skeletal diseases and abnormal mouse skeletal phenotypes. Genetic correlation and genomic structural equation modeling indicated that limb proportions exhibited strong genetic sharing but were genetically independent of width and torso proportions. Phenotypic and polygenic risk score analyses identified specific associations between osteoarthritis (OA) of the hip and knee, the leading causes of adult disability in the United States, and skeletal proportions of the corresponding regions. We also found genomic evidence of evolutionary change in arm-to-leg and hip-width proportions in humans consistent with striking anatomical changes in these skeletal proportions in the hominin fossil record. In contrast to cardiovascular, auto-immune, metabolic, and other categories of traits, loci associated with these skeletal proportions are significantly enriched in human accelerated regions (HARs), and regulatory elements of genes differentially expressed through development between humans and the great apes. Taken together, our work validates the use of deep learning models on DXA images to identify novel and specific genetic variants affecting the human skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.

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Section: Resultsmentioning

confidence: 99%

The genetic architecture of the human skeletal form

Kun

Javan

Smith

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Similarly, a common variant (rs1891308) near ADGRG6 , which encodes a G protein–coupled receptor, is associated with increased torso length. Mice with conditional knockouts in ADGRG6 have spine abnormalities that reduce torso length ( 48 ). Thus, our GWAS of SPs identifies genes that were previously associated with skeletal developmental biology and Mendelian skeletal phenotypes, demonstrating the potential for future functional and knockout studies.…”

Section: Resultsmentioning

confidence: 99%

The genetic architecture and evolution of the human skeletal form

Kun

Javan

Smith

et al. 2023

Science

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The human skeletal form underlies bipedalism, but the genetic basis of skeletal proportions (SPs) is not well characterized. We applied deep-learning models to 31,221 x-rays from the UK Biobank to extract a comprehensive set of SPs, which were associated with 145 independent loci genome-wide. Structural equation modeling suggested that limb proportions exhibited strong genetic sharing but were independent of width and torso proportions. Polygenic score analysis identified specific associations between osteoarthritis and hip and knee SPs. In contrast to other traits, SP loci were enriched in human accelerated regions and in regulatory elements of genes that are differentially expressed between humans and great apes. Combined, our work identifies specific genetic variants that affect the skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.

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“…In addition, Gpr126 deficiency also leads to multiple defects in peripheral nerves [104], inner ear (in zebrafish) [105], placental development [106], and lack of myelination in the peripheral nervous system (PNS) [107]. More recent studies in cell typespecific Gpr126 knock out animals further indicated a role for GPR126 in the regulation of body length and bone mass as well as the maintenance of spinal alignment [108,109]. In line with these, GPR126 mutations and/or genetic variants in humans are associated with several disorders, including adolescent idiopathic scoliosis [110], arthrogryposis multiplex congenita [111], and intellectual disability [112].…”

Section: Adgrg6/gpr126mentioning

confidence: 99%

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

Lin

Chen

et al. 2022

Pharmaceuticals

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Cells respond to diverse types of mechanical stimuli using a wide range of plasma membrane-associated mechanosensitive receptors to convert extracellular mechanical cues into intracellular signaling. G protein-coupled receptors (GPCRs) represent the largest cell surface protein superfamily that function as versatile sensors for a broad spectrum of bio/chemical messages. In recent years, accumulating evidence has shown that GPCRs can also engage in mechano-transduction. According to the GRAFS classification system of GPCRs, adhesion GPCRs (aGPCRs) constitute the second largest GPCR subfamily with a unique modular protein architecture and post-translational modification that are well adapted for mechanosensory functions. Here, we present a critical review of current evidence on mechanosensitive aGPCRs.

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An adhesion G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

Cited by 19 publications

References 81 publications

The genetic architecture of the human skeletal form

The genetic architecture of the human skeletal form

The genetic architecture and evolution of the human skeletal form

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

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