Rare coding variants in collagen genes increase risk of adolescent idiopathic scoliosis. G. Haller1, D. Alvarado1, J. Buchan1, K. McCall1, P. Yang1, C. Cruchaga3, M. Harms2, A. Goate3, M. Willing4, E. Baschal5, N. Miller5, C. Wise6,7,8,9, M. Dobbs1,10, C. Gurnett1,2,4 1) Department of Orthopaedic Surgery, Washington University School of Medicine, Saint Louis, MO; 2) Department of Neurology, Washington University School of Medicine, Saint Louis, MO; 3) Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO; 4) Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO; 5) Department of Orthopaedic Surgery, University of Colorado, Denver, CO; 6) Department of Orthopaedic Surgery, Texas Southwestern Medical Center at Dallas, Dallas, TX; 7) Department of Pediatrics, Texas Southwestern Medical Center at Dallas, Dallas, TX; 8) McDermott Center for Human Growth and Development, Texas Southwestern Medical Center at Dallas, Dallas, TX; 9) Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX; 10) Shriners Hospital for Children, Saint Louis, MO.

   Adolescent idiopathic scoliosis (AIS) is the most common form of childhood spinal deformity, affecting ~3% of the population. Unfortunately, little is known of its etiology or genetic basis. To understand the role of rare variants in AIS, exome sequence data was generated for 154 unrelated AIS cases. We observed novel heterozygous mutations in musculoskeletal collagen genes in 32% (49/154) of unrelated affected individuals with AIS compared with 12% (508/4300) of controls (P = 2.8 10-8, Fishers exact test), a finding which was strengthened by addition of Sanger sequenced family members (P = 2 x 10-14, FamSKAT). Additionally, we observed significantly more rare musculoskeletal collagen gene coding variants per person among AIS cases compared to controls (1.9 vs. 1.2 variants, t-test p = 2.3 x 10-8) which remained significant after removal of individuals harboring novel variants (1.8 vs. 1.1 variants, t-test p = 3.5 x 10-7), suggesting a polygenic burden of collagen rare variants. We validated these findings by resequencing a subset of six musculoskeletal collagen genes in a second cohort of AIS patients, and again observed significantly more novel variants per gene as well as a significantly higher burden of rare missense variants per individual in AIS cases compared with controls. Examination of the functional effects of two novel AIS-associated variants (COL1A1 His48Glu and COL1A2 Pro1016His) in vitro revealed increased intracellular type I procollagen compared to WT, suggesting a collagen processing defect. Overall, our analysis suggests that as much as 10% of AIS can be explained by collagen gene variation. These results establish alterations in a subset of collagen genes as a major genetic risk factor for AIS.

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