Cristina M. Justice

Familial idiopathic scoliosis: evidence of an X-linked susceptibility locus.

Study Design. A genomic screen and statistical linkage analysis of a large sample of families with individuals having idiopathic scoliosis was performed. Objectives. To identify an X-linked susceptibility locus involved in the expression of familial idiopathic scoliosis. Summary of Background Data. A large sample of families with individuals having idiopathic scoliosis (202 families; 1198 individuals) were diagnosed through physical examination and radiographic criteria, and genomic screening and genetic linkage analyses were performed. Methods. Model-independent linkage analysis was used to screen genotyping data from 15 X-linked markers in 202 families (1198 individuals). Families were stratified based on the ratio of the likelihood of an X-linked dominant (XLD) inheritance model relative to that of an autosomal dominant (AD) model. Both model-independent and model-dependent linkage analyses were used to identify potential candidate regions. Results. When the entire set of families were analyzed with model-independent methods, no result was significant at the 0.05 level for any of the markers. However, when the families were stratified based on the ratio of the likelihood of the X-linked dominant to autosomal dominant mode of inheritance, results from model-dependent linkage analysis of 15% of the families most likely to have X-linked dominant inheritance showed six adjacent markers with positive lod score values and a maximum lod score of 1.69 (&thgr; = 0.2) at marker GATA172D05. A lod score of 2.23 at this same marker was found in a single family with six affected individuals. Conclusion. The results suggest that a region on the X chromosome may be linked to the expression of familial idiopathic scoliosis in a subset of these families.

Identification of candidate regions for familial idiopathic scoliosis

Study Design. A genomic screen and statistical linkage analysis of 202 families with at least two individuals with idiopathic scoliosis was performed. Objectives. To identify candidate regions or the autosomal loci that may be involved in the expression of familial idiopathic scoliosis. Summary of Background Data. A large sample of families with individuals having idiopathic scoliosis (202 families; 1,198 individuals) was ascertained; diagnoses were based on physical examination and radiographic criteria. Methods. Model-independent linkage analysis of qualitative and quantitative traits (degree of lateral curvature) related to scoliosis was used to screen genotyping data from 391 markers in the 202 families. Subsets of families were determined before genotyping based on the most likely mode of inheritance for each family (autosomal dominant vs. X-linked dominant). Fine mapping results corroborated linkage in the primary candidate regions. Results. Candidate regions on chromosomes 6, 9, 16, and 17 were considered to have the strongest evidence for linkage across all subsets considered. Conclusion. Linkage analyses have identified several candidate regions, a significant step in defining the genetic etiology of this disorder.

Idiopathic Scoliosis : Identification of Candidate Regions on Chromosome 19p13

Study Design. We performed genomic screening, statistical linkage analysis, and fine mapping of 202 families with at least 2 individuals with idiopathic scoliosis. Objective. To identify regions on chromosome 19p13 statistically linked to the phenotypic expression of idiopathic scoliosis. Summary of Background Data. Idiopathic scoliosis is a common structural curvature of the spine affecting otherwise healthy children. Presently, no clear consensus exists regarding the underlying abnormality or genetic determinants of this disease. Methods. Model-independent linkage analysis of qualitative and quantitative traits related to scoliosis was used to screen genotyping data from 391 markers in 202 families (1198 individuals). Subsets of families with probands having a curve ≥30° were dichotomized based on the most likely mode of inheritance for each family (autosomal dominant or X-linked dominant). Fine mapping was performed to show linkage to candidate regions on chromosome 19. Results. When the threshold of disease was set at a curvature of ≥30°, qualitative linkage analysis revealed significant results at 2 successive markers on chromosome 19. Conclusion. The data confirm a previously reported genetic locus on chromosome 19 as potentially significant in the etiology of idiopathic scoliosis.

A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9

Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10−14, odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10−11, OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10−10, OR = 0.19) and rs17724206 (P = 1.50 × 10−8, OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 × 10−31 and rs10262453, P = 3.50 × 10−14) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC.

Lack of association between the aggrecan gene and familial idiopathic scoliosis.

Study Design. A study was conducted to determine the potential association between a specific aggrecan gene polymorphism and familial idiopathic scoliosis (FIS). Objectives. To determine the allelic distribution of the exon 12 polymorphism within a sample of families with FIS. Summary of Background Data. FIS is a structural curvature of the spine where the underlying genetic etiology has not been established. The aggrecan locus has been linked to multiple skeletal disorders. A polymorphism, within the aggrecan gene, was previously reported to be associated with curve severity in individuals with scoliosis. Methods. Fifty-eight families with FIS were genotyped for the aggrecan exon 12 polymorphism using a polymerase chain reaction method. Model-independent sib-pair linkage analyses and tests of association were performed to analyze the genetic effects of the exon 12 polymorphism. Results. Linkage analyses of a genomic screen performed on a subgroup of 48 families with a most likely to be X-linked dominant mode of inheritance of FIS showed marginally significant results on chromosome 15q25-26 (P < 0.05). The overall distribution of the alleles was consistent with previously reported literature; no evidence of association and marginal significance of linkage was found between the polymorphism and FIS or the degree of lateral curvature. Conclusions. Despite the negative association reported here, further investigation of the gene and its potential association to FIS is required.

Linkage analysis of genetic loci for kyphoscoliosis on chromosomes 5p13, 13q13.3, and 13q32†

Kyphoscoliosis, a three‐dimensional deformity of spinal growth, is characterized by a curvature in the coronal plane (scoliosis) in conjunction with thoracic kyphosis in excess of the normal range in the sagittal plane. We identified kyphoscoliosis within members of seven families (53 individuals) originally ascertained as part of a large collaborative study of familial idiopathic scoliosis. Model‐independent linkage analysis of a genome‐wide microsatellite screen identified areas suggestive of linkage on chromosomes 2q22, 5p13, 13q, and 17q11. Single‐point and multipoint analyses of an additional 25 flanking microsatellite markers corroborated linkage to these regions, with areas on chromosomes 5p13, 13q13, and 13q32 being the most significant (P < 0.005). Analyses of single nucleotide polymorphism (SNP) markers in the candidate region on chromosome 5 narrowed the region to approximately 3.5 Mb (P < 0.05), with the most significant P values (P < 0.01) occurring in approximately a 1.3‐Mb region. Candidate loci in this region include IRX1, IRX2, and IRX4 of the Iroquois Homeobox protein family. On chromosome 13, single‐point and multipoint analyses resulted in multiple SNPs having P values < 0.05 within five candidate genes: Osteoblast‐specific factor 2 or periostin, forkhead box O1A, A‐kinase anchor protein 11, TBC1 domain family member 4, and glypican 5, thus supporting the potential relevance of this region in the pathogenesis of kyphoscoliosis.

Comparison of year-of-exam- and age-matched estimates of heritability in the Framingham Heart Study data.

Several different approaches can be used to examine generational and temporal trends in family studies. The measurement of offspring and parents can be made over a short period of time with parents and offspring having quite different ages, or measurements can be made at the same ages but with decades between parent and offspring measures. A third approach, used in the Framingham Heart Study, has repeated examinations across a broad range of age and time, and provides a unique opportunity to compare these approaches. Parents and offspring were matched both on (year of exam) and on age. Heritability estimates for systolic blood pressure, body mass index, height, weight, cholesterol, and glucose were obtained by regressing offspring on midparent values with and without adjustment for age. Higher estimates of heritability were obtained for age-matched than for year-of-exam-matched data for all traits considered. For most traits, estimates of the heritability of the change over time (slope) of the trait were near zero. These results suggest that the optimal design to identify genetic effects in traits with large age-related effects may be to measure parents and offspring at similar ages and not to rely on age-adjustment or longitudinal measures to account for these temporal effects.

Males with familial idiopathic scoliosis: a distinct phenotypic subgroup.

Study Design. Statistical analysis of genomic screening and fine mapping data. Objective. The goals of this study were to analyze a region on chromosome 17 and to identify specific genetic determinants within this region linked to familial idiopathic scoliosis (FIS) in a subgroup of families in which affected males have undergone surgery. Summary of Background Data. The high prevalence and variability of FIS is indicative of genetic heterogeneity. To localize genes related to scoliosis, identification of groups of families with common clinical characteristics is a strategy that reduces genetic heterogeneity. Two independent studies have implicated a region on chromosome 17 as related to FIS. Methods. With approval of the Institutional Review Board, the initial study population consisted of 202 families (1198 individuals), each of which had 2 or more affected individuals; 17 of those families had an affected male who had surgery. Individuals underwent genomic screening and subsequent fine mapping. Results were obtained using model-independent linkage analysis, with scoliosis set as a qualitative and as a quantitative trait, as implemented in SIBPAL (S.A.G.E., v4.5). The level of significance was set at P ≤ 0.05. Results. The initial study population had significant results at markers d17s975 and d17s2196. Analyses of a subgroup of families with males having undergone surgery using a customized single nucleotide polymorphism panel resulted in increased significance of this region. Conclusion. The data confirm a previously reported genetic locus on chromosome 17 as statistically significant in the etiology of FIS within a subgroup of families in which an affected male had spinal surgery.

Intra-Familial Tests of Association between Familial Idiopathic Scoliosis and Linked Regions on 9q31.3-q34.3 and 16p12.3-q22.2

Objective: Custom genotyping of markers in families with familial idiopathic scoliosis were used to fine-map candidate regions on chromosomes 9 and 16 in order to identify candidate genes that contribute to this disorder and prioritize them for next-generation sequence analysis. Methods: Candidate regions on 9q and 16p–16q, previously identified as linked to familial idiopathic scoliosis in a study of 202 families, were genotyped with a high-density map of single nucleotide polymorphisms. Tests of linkage for fine-mapping and intra-familial tests of association, including tiled regression, were performed on scoliosis as both a qualitative and quantitative trait. Results and Conclusions: Nominally significant linkage results were found for markers in both candidate regions. Results from intra-familial tests of association and tiled regression corroborated the linkage findings and identified possible candidate genes suitable for follow-up with next-generation sequencing in these same families. Candidate genes that met our prioritization criteria included FAM129B and CERCAM on chromosome 9 and SYT1, GNAO1, and CDH3 on chromosome 16.

Identification of Susceptibility Loci for Scoliosis in FIS Families With Triple Curves

The triple curve pattern (three lateral curvatures of equal severity) has been recognized as a distinct and unique clinical subtype of scoliosis. As part of a large study of familial idiopathic scoliosis (FIS), a subset of five families with a triple curve pattern (at least one member of each family having a triple curve) was evaluated to determine if this curve pattern was linked to any of the markers previously genotyped as part of the STRP‐based previous linkage screen. Model independent linkage analysis (SIBPAL, v4.5) of the initial genomic screen identified candidate regions on chromosomes 6 and 10 when FIS was analyzed both as qualitative and quantitative traits in single‐ and multipoint linkage analyses. Additional fine mapping analyses of this subgroup with SNPs corroborated the findings in these regions (P < 0.001). These regions have been previously linked to FIS, however, this is the first time these regions have been implicated in a clinically well‐defined subgroup and may suggest a unique genetic etiology for the formation of a triple curve.