Adolescent idiopathic scoliosis (AIS) affects up to 3% of children worldwide. It has been known for many decades that the female-to-male ratio is about 2:1 for minor curves whereas the ratio increases with increasing curve severity, reaching about 10:1 for curves of >30°. The molecular mechanisms that account for the predominance of females in the progressive and severe forms of AIS are currently unknown. Kruse et al. provide results of their quantitative genetic analyses of families with AIS that support a polygenic threshold model with sex dimorphism.
Before commenting on the accompanying paper, there is a need to consider gene-variant effect sizes and the modes of inheritance of musculoskeletal and other disorders. In the past decade, rapid advances in genetic information and technology have enabled many new disease-associated genes to be identified in patients with skeletal dysplasias of unknown cause. The skeletal dysplasias include many hundreds of traits that usually follow Mendelian patterns of inheritance of single-gene disorders. In such traits, the gene-variant effect sizes are often large. Many studies have shown that very severe and lethal phenotypes, including those involving scoliosis, are often associated with very large single-gene-variant effect sizes. In such children, the adverse effects of the single gene mutations overwhelm any potentially beneficial effects of protective gene variants and environmental factors. However, families with milder Mendelian traits often have smaller single-gene-variant effect sizes and more marked variation in phenotypic severity. It is likely that the variation in severity of the phenotypes in such families is determined, at least in part, by the influence of other positive and negative gene variants and environmental factors. As the disease-gene-variant effect sizes decrease further, as in many common disorders such as osteoporosis and osteoarthritis, the mode of inheritance changes from the Mendelian inheritance of single-gene disorders to polygenic inheritance.
Although some previous studies of AIS suggested autosomal-dominant or X-linked modes of Mendelian inheritance of single-gene variants, more recent studies using larger numbers of families and modern methods of genetic analysis favor polygenic inheritance1,2. The accompanying paper by Kruse et al. provides evidence supporting polygenic inheritance of AIS. Of particular importance, the accompanying paper also provides genetic evidence of sex dimorphism whereby transmission of AIS was lowest in sons of affected mothers (36%) and greatest in daughters of affected fathers (85%). Sisters of affected males were also much more likely to be affected (77%) than brothers of affected females (20%). These findings suggest a polygenic threshold model in which the development of AIS in males requires the inheritance of a greater number of contributing factors or more robust contributing factors than in females. This concept of a threshold beyond which there is a risk of malformation is referred to as the Carter effect as a result of the general models of polygenic inheritance developed by Carter3 and Fraser4. The proposal by Kruse et al. that AIS is associated with a polygenic threshold model with sex dimorphism is supported by similar findings in extended families with AIS in Utah2. The latter study also provided evidence for a mixed model of inheritance of AIS that is primarily polygenic but has a major recessive-gene component.
The study by Kruse et al. was restricted to patients with >20° of structural scoliosis and onset of the scoliosis on or after the age of ten years. Offspring under the age of fourteen years were excluded because their affected status could not be determined. The study was limited to multiplex families containing more than one affected member. Individuals were excluded if they had a diagnosis known to cause scoliosis. All of these inclusion and exclusion criteria are appropriate, but the results may therefore only apply to this type of study population. The paper by Kruse et al. does not include information about the onset, progression, severity, type, or location of the AIS deformities in their study population. Evidence from other studies indicates that genetic factors may separately govern the timing, progression, severity, type, and location of the AIS deformities. The genetic control of these parameters may involve separate or overlapping sets of genes. Although AIS occurs worldwide, ethnic diversity may also play an important role in the genetic and environmental aspects of AIS2.
Despite the above limitations, the paper by Kruse et al. offers some exciting possibilities for ongoing studies to characterize the underlying genetic variants that account for the different malformation thresholds in females and males. Previous genome-wide association studies have identified many regions of the genome that may contain gene variants associated with AIS, including some genes involved in axon guidance pathways1. However, future genetic analyses are likely to be substantially enhanced by comparisons of the genomes of affected and unaffected males and females in multiplex families using copy-number variant analyses and exome sequencing of their genomes. Copy-number variant analyses are microarray or chip analyses that quantify the numbers of copies of each gene. Traditionally each gene has two copies, but there may be one or zero copies because of a microdeletion, or more than two copies because of a microduplication. The association of copy-number variants with male or female thresholds for AIS will enable a search for other types of gene variants in patients who have both copies of the gene. For example, if some patients show a loss of one or two copies of a gene, other patients with both copies may show loss-of-function mutations of the gene. Alternatively, if some patients have more than two copies of a gene, other patients with two copies may have gain-of-function mutations of the gene. Exome sequencing involves sequencing the protein-encoding parts of all genes. It is a powerful genetic tool for the identification of genetic variants associated with rare and common phenotypes. The combination of copy-number variant analyses and exome sequencing of males and females with AIS has a high likelihood of identifying some of the gene variants that account for the polygenic threshold model with sex dimorphism observed by Kruse et al. in their cohort of multiplex families with AIS. The functional consequences of the genetic variants will also need to be studied in various model systems.
Identification of gene variants associated with various aspects of the etiology and pathogenesis of AIS is critical to future advances in clinical care. Although important advances in nonoperative and operative care of AIS continue, there is an urgent need to gain a better understanding of the molecular mechanisms involved in the onset, progression, severity, location, and patterns of the AIS deformities. Further genetic analyses, based on the report by Kruse et al. and those by other investigators, may reveal genetic variants in signaling or other pathways that suppress the progression and severity of AIS. With the increasing availability of antibodies and pharmaceuticals that modulate many pathways in humans, there is a strong likelihood that suitable agents will be available for clinical trials in patients with AIS. Clinical and genetic analyses appropriate for various ethnic populations, are also likely to be needed to identify those patients with the highest likelihood of scoliosis progression for inclusion in such trials. The duration of such trials is another consideration, but the trials would presumably stop at or shortly after skeletal maturity.