title: Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis.
abstract: Adolescent idiopathic scoliosis (AIS) is a clinically significant disorder with high heritability that affects 2-4% of the population. Genome-wide association studies have identified LBX1 as a strong susceptibility locus for AIS in Asian and Caucasian populations. Here we further dissect the genetic association with AIS in a Caucasian population. To identify genetic markers associated with AIS we employed a genome-wide association study (GWAS) design comparing 620 female Caucasian patients who developed idiopathic scoliosis during adolescence with 1,287 ethnically matched females who had normal spinal curves by skeletal maturity. The genomic region around LBX1 was imputed and haplotypes investigated for genetic signals under different inheritance models. The strongest signal was identified upstream of LBX1 (rs11190878, P(trend) = 4.18 × 10(-9), OR = 0.63[0.54-0.74]). None of the remaining SNPs pass the genome-wide significance threshold. We found rs11190870, downstream of LBX1 and previously associated with AIS in Asian populations, to be in modest linkage disequilibrium (LD) with rs11190878 (r(2) = 0.40, D' = 0.81). Haplotype analysis shows that rs11190870 and rs11190878 track a single risk factor that resides on the ancestral haplotype and is shared across ethnic groups. We identify six haplotypes at the LBX1 locus including two strongly associated haplotypes; a recessive risk haplotype (TTA, Control(freq) = 0.52, P = 1.25 × 10(-9), OR = 1.56), and a co-dominant protective haplotype (CCG, Control(freq) = 0.28, P = 2.75 × 10(-7), OR = 0.65). Together the association signals from LBX1 explain 1.4% of phenotypic variance. Our results identify two clinically relevant haplotypes in the LBX1-region with opposite effects on AIS risk. The study demonstrates the utility of haplotypes over un-phased SNPs for individualized risk assessment by more strongly delineating individuals at risk for AIS without compromising the effect size.
authors: Affiliated Genetics, Inc., Salt Lake City, Utah, 84109, United States of America.
authors: Rakesh
authors: R
authors: Chettier
authors: Affiliated Genetics, Inc., Salt Lake City, Utah, 84109, United States of America.
authors: Lesa
authors: L
authors: Nelson
authors: Lucina Foundation, Salt Lake City, Utah, 84109, United States of America.
authors: James W
authors: JW
authors: Ogilvie
authors: Juneau Biosciences, LLC., Salt Lake City, Utah, 84109, United States of America.
authors: Hans M
authors: HM
authors: Albertsen
authors: Affiliated Genetics, Inc., Salt Lake City, Utah, 84109, United States of America; Juneau Biosciences, LLC., Salt Lake City, Utah, 84109, United States of America.
authors: Kenneth
authors: K
authors: Ward
mesh_terms: D000293:Adolescent; D000483:Alleles; D016022:Case-Control Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012600:Scoliosis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C542809:LBX1 protein, human; D014157:Transcription Factors