Chettier Rakesh, Nelson Lesa, Ogilvie James W, Albertsen Hans M, Ward Kenneth
Affiliated Genetics, Inc., Salt Lake City, Utah, 84109, United States of America.
Lucina Foundation, Salt Lake City, Utah, 84109, United States of America.
PLoS One. 2015 Feb 12;10(2):e0117708. doi: 10.1371/journal.pone.0117708. eCollection 2015.
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.
青少年特发性脊柱侧凸（AIS）是一种具有高遗传性的临床重要疾病，影响着2%-4%的人群。全基因组关联研究已确定LBX1是亚洲和白种人群中AIS的一个强易感基因座。在此，我们进一步剖析白种人群中与AIS的遗传关联。为了鉴定与AIS相关的遗传标记，我们采用全基因组关联研究（GWAS）设计，比较了620名青春期患特发性脊柱侧凸的白种女性患者和1287名骨骼成熟时脊柱曲线正常的种族匹配女性。对LBX1周围的基因组区域进行了推算，并研究了单倍型在不同遗传模型下的遗传信号。在LBX1上游发现了最强信号（rs11190878，P(trend)=4.18×10(-9)，OR=0.63[0.54-0.74]）。其余单核苷酸多态性（SNP）均未达到全基因组显著性阈值。我们发现位于LBX1下游且先前在亚洲人群中与AIS相关的rs11190870与rs11190878存在中等程度的连锁不平衡（LD）（r(2)=0.40，D'=0.81）。单倍型分析表明，rs11190870和rs11190878追踪一个单一风险因素，该因素存在于祖先单倍型上且在不同种族中共享。我们在LBX1基因座鉴定出六种单倍型，包括两种强相关单倍型；一种隐性风险单倍型（TTA，对照组频率=0.52，P=1.25×10(-9)，OR=1.56），以及一种共显性保护单倍型（CCG，对照组频率=0.28，P=2.75×10(-7)，OR=0.65）。来自LBX1的关联信号共同解释了1.4%的表型变异。我们的结果在LBX1区域鉴定出两种对AIS风险有相反影响的临床相关单倍型。该研究证明了单倍型相对于未分型SNP在个体风险评估中的效用，通过更有力地界定AIS风险个体而不影响效应大小。
