Healthy_back (healthy_back) wrote,

Наследственность при сколиозе. Вторая ссылка - матаанализ

Грубо говоря, ничего нового: 38 % - генетика (даже не генотип, а фенотип), 62 % - среда. То, что определённых генов выделить не могут - это уже давно известно. Могут смотреть дедовским способом - есть ли больные в роду. Да, такая связь есть, и она существенная. Просто исследования посвежее. Интересно, что и болеют в основном женщины, и передача в основном происходит через женщин.

Я все время забываю про дефицит меди при сколиозе, хотя сам же 10 лет назад давал ссылки. (, ( При всех протоколах добавок витаминов хоть при гипотиреозе, хоть при аутизме, хоть "общем" про медь никто ничего не говорит. Как и про анализ церулоплазмина.

Копирую пару статей на английском, просто источники хорошего качества.

Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:0-6,900,000

▼ Description

Idiopathic scoliosis is a structurally fixed lateral curvature of the spine with a rotatory component. There is at least a 10 degree curvature as demonstrated by upright spine roentgenograms by the Cobb method (Weinstein, 1994).

Scoliosis may occur secondary to other hereditary disorders including Marfan syndrome (154700), dysautonomia (223900), neurofibromatosis (see 162200), Friedreich ataxia (see 229300), and muscular dystrophies.

Genetic Heterogeneity of Susceptibility to Isolated Scoliosis

Loci for isolated scoliosis have been mapped to chromosome 19 (IS1), chromosome 17 (IS2; 607354), chromosome 8 (IS3; 608765), chromosome 9q31-q34 (IS4; 612238), and chromosome 17q25-qter (IS5; 612239).

▼ Inheritance

De George and Fisher (1967) could not find evidence for operation of simple genetic factors for scoliosis. High concordance in both monozygotic and dizygotic twins and an excess of propositi born to older mothers suggested to these workers that maternal factors predominate.

Wynne-Davies (1968) favored either dominant or multifactorial inheritance. Dominant inheritance was suggested by Faber (1936), by Garland (1934) who observed the condition in 5 generations, and by Gilly et al. (1963).

Male-to-male transmission is apparently rare and was specifically absent in 17 families studied by Cowell et al. (1972), who suggested X-linked dominant inheritance. The 8 to 1 ratio of females to males supports this conclusion. Connor et al. (1987) did a systematic study of 87 families with early-onset scoliosis. Bell and Teebi (1995) described a French Canadian family in which a father and 2 daughters had idiopathic scoliosis. The parents were not known to be related.

Axenovich et al. (1999) performed segregation analysis on 101 pedigrees ascertained through a proband with idiopathic scoliosis, using a model with age and gender effects. When they analyzed the pedigrees defining affected status as persons with a Cobb angle of more than 5 degrees, they detected no significant major gene effect. However, when the affected status was assigned only to persons with pronounced forms of disease (a curve of at least 11 degrees), a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex- and age-dependent penetrance of genotypes.

Inoue et al. (1998) studied idiopathic scoliosis in 21 pairs of twins in whom DNA fingerprinting was used to establish monozygosity in 13 and dizygosity in 8. There was concordance for idiopathic scoliosis in 92.3% of monozygotic and 62.5% of dizygotic twins. Of the 12 pairs of monozygotic twins concordant for idiopathic scoliosis, 6 showed discordant curve patterns.

In a study of 69 extended Utah families with a history of adolescent idiopathic scoliosis, including a total of 247 affected individuals with disease confirmed by x-rays and medical records, Ward et al. (2010) concluded that the condition is polygenic and multifactorial. Excluding all probands and assuming autosomal dominant inheritance, 1,260 individuals over the age of 16 years were determined to be at risk because they had a parent with AIS. Assuming 50% of those individuals carried the allele, estimated penetrance in at-risk males was approximately 9%, whereas that for at-risk females was approximately 29%. The lowest recurrence risk calculated, for third-degree relatives, was still an average of 9%, well above the general population's risk. Onset of AIS appeared to be inherited separately from curve pattern and severity. In a study of phenotypes in 36 of the families, affected individuals were consistent in either curve severity or curve pattern, but not both. The authors stated that it was unclear whether severity or pattern was more heritable, but that the location of the curve on the spine might be the most heritable trait of the phenotype. Ward et al. (2010) concluded that AIS is genetically complex, with low penetrance of cumulative alleles and variable expression.

▼ Mapping

Chan et al. (2002) studied 7 unrelated multiplex families of Chinese descent with adolescent idiopathic scoliosis, comprising 25 affected members, and performed a genomewide scan with more than 400 fluorescent microsatellite markers. Multipoint linkage analysis revealed significant linkage to the distal short arm of chromosome 19, with both a maximum multipoint lod score and a nonparametric lod score of 4.93. Two-point linkage analysis gave a lod score of 3.63 at a recombination fraction of 0.00 at D19S216. Refinement placed the locus in a region spanning 5.2 cM on the sex-averaged genetic map on 19p13.3.

Associations Pending Confirmation

In 5 families with at least 2 individuals with scoliosis, one of whom in each family had 'triple-curve' scoliosis, in which affected individuals had 3 distinct scoliotic curves that each measured at least 10 degrees, Marosy et al. (2010) performed genomewide linkage analysis and identified the most significant values for D6S1065 on chromosome 6q (p less than 2.0 x 10(-10)) and for D10S677 on chromosome 10q (p less than 5.0 x 10(-7)). Fine mapping with SNPs narrowed the loci to a 1.0-Mb interval on chromosome 6q and a 7.0-Mb interval on chromosome 10q (p less than 0.001).

▼ Molecular Genetics

Associations Pending Confirmation

Ogura et al. (2015) performed a genomewide association study (GWAS) of 2,109 affected subjects with adolescent idiopathic scoliosis compared with 11,140 control subjects. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, Ogura et al. (2015) identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 x 10 (13), OR = 1.21, 95% CI 1.15-1.27). The most significantly associated SNPs were in intron 3 of BNC2 (608669), which encodes the zinc finger transcription factor basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs had the potential to regulate BNC2 transcription activity and that susceptibility alleles increased BNC2 expression. Ogura et al. (2015) identified a functional SNP, rs10738445, in BNC2 whose susceptibility allele showed both higher binding to a transcription factor, YY1 (600013), and higher BNC2 enhancer activity than the nonsusceptibility allele. Finally, Ogura et al. (2015) showed that BNC2 overexpression produced body curvature in developing zebrafish in a gene dosage-dependent manner. Ogura et al. (2015) concluded that increased BNC2 expression is implicated in the etiology of adolescent idiopathic scoliosis.

For discussion of a possible association between scoliosis and variation in the POC5 gene, see 617880.

▼ Animal Model

Opsahl et al. (1984) showed an inverse relationship between the amount of copper in the diet and the severity and incidence of scoliosis in scoliosis-prone chickens.

▼ See Also:
Bushell et al. (1980)


Axenovich, T. I., Zaidman, A. M., Zorkoltseva, I. V., Tregubova, I. L., Borodin, P. M. Segregation analysis of idiopathic scoliosis: demonstration of a major gene effect. Am. J. Med. Genet. 86: 389-394, 1999. [PubMed: 10494097, related citations] [Full Text]

Bell, M., Teebi, A. S. Autosomal dominant idiopathic scoliosis? (Letter) Am. J. Med. Genet. 55: 112 only, 1995. [PubMed: 7702081, related citations] [Full Text]

Bushell, G. R., Ghosh, P., Taylor, T. K. F. Collagen defect in idiopathic scoliosis. (Letter) Lancet 312: 94-95, 1980. Note: Originally Volume II. [PubMed: 78312, related citations] [Full Text]

Chan, V., Fong, G. C. Y., Luk, K. D. K., Yip, B., Lee, M.-K., Wong, M.-S., Lu, D. D. S., Chan, T.-K. A genetic locus for adolescent idiopathic scoliosis linked to chromosome 19p13.3. Am. J. Hum. Genet. 71: 401-406, 2002. [PubMed: 12094330, images, related citations] [Full Text]

Connor, J. M., Conner, A. N., Connor, R. A. C., Tolmie, J. L., Yeung, B., Goudie, D. Genetic aspects of early childhood scoliosis. Am. J. Med. Genet. 27: 419-424, 1987. [PubMed: 3300334, related citations] [Full Text]

Cowell, H. R., Hall, J. N., MacEwen, G. D. Genetic aspects of idiopathic scoliosis. Clin. Orthop. Relat. Res. 86: 121-131, 1972. [PubMed: 5047777, related citations] [Full Text]

De George, F. V., Fisher, R. L. Idiopathic scoliosis: genetic and environmental aspects. J. Med. Genet. 4: 251-257, 1967. [PubMed: 6082901, related citations] [Full Text]

Faber, A. Untersuchungen ueber die Erblichkeit der Skoliose. Arch. Orthop. Unfallchir. 36: 217-296, 1936.

Garland, H. G. Hereditary scoliosis. Brit. Med. J. 1: 328 only, 1934. [PubMed: 20778092, related citations] [Full Text]

Gilly, R., Stagnara, P., Frederich, A., Dalloz, C., Robert, J. M., Goldblatt, B. Medical aspects of essential structural scoliosis in children. Lyon Med. 95: 79-95, 1963. [PubMed: 13947961, related citations]

Inoue, M., Minami, S., Kitahara, H., Otsuka, Y., Nakata, Y., Takaso, M., Moriya, H. Idiopathic scoliosis in twins studied by DNA fingerprinting: the incidence and type of scoliosis. J. Bone Joint Surg. Br. 80: 212-217, 1998. [PubMed: 9546446, related citations] [Full Text]

Marosy, B., Justice, C. M., Vu, C., Zorn, A., Nzegwu, N., Wilson, A. F., Miller, N. H. Identification of susceptibility loci for scoliosis in FIS families with triple curves. Am. J. Med. Genet. 152A: 846-855, 2010. [PubMed: 20358593, images, related citations] [Full Text]

Ogura, Y., Kou, I., Miura, S., Takahashi, A., Xu, L., Takeda, K., Takahashi, Y., Kono, K., Kawakami, N., Uno, K., Ito, M., Minami, S., and 23 others. A functional SNP in BNC2 is associated with adolescent idiopathic scoliosis. Am. J. Hum. Genet. 97: 337-342, 2015. [PubMed: 26211971, images, related citations] [Full Text]

Opsahl, W., Abbott, U., Kenney, C., Rucker, R. Scoliosis in chickens: responsiveness of severity and incidence to dietary copper. Science 225: 440-442, 1984. [PubMed: 6740317, related citations] [Full Text]

Ward, K., Ogilvie, J., Argyle, V., Nelson, L., Meade, M., Braun, J., Chettier, R. Polygenic inheritance of adolescent idiopathic scoliosis: a study of extended families in Utah. Am. J. Med. Genet. 152A: 1178-1188, 2010. [PubMed: 20425822, related citations] [Full Text]

Weinstein, S. L. The thoracolumbar spine. In: Weinstein, S. L.; Buckwalter, J. A. (eds.): Turek's Orthopaedics: Principles and Their Application. (5th ed.) Philadelphia: J. P. Lippincott Company (pub.) 1994. Pp. 447-485.

Wynne-Davies, R. Familial idiopathic scoliosis: a family survey. J. Bone Joint Surg. Br. 50: 24-30, 1968. [PubMed: 5641594, related citations]
Eur Spine J. 2012 Oct; 21(10): 1905–1919.
Published online 2012 Jun 14. doi: 10.1007/s00586-012-2389-6
PMCID: PMC3463687
PMID: 22695700
The genetic epidemiology of idiopathic scoliosis
Kristen Fay Gorman,1,2 Cédric Julien,1,2 and Alain Moreaucorresponding author1,2,3

Idiopathic scoliosis (IS) is a complex developmental syndrome that constitutes the largest subgroup of human spinal curvatures [Online Mendelian Inheritance in Man (OMIM): 181800]. First described by Hippocrates in On the Articulations (Part 47), IS has been the subject of ongoing research, and yet its etiology remains enigmatic. IS is marked by phenotypic complexity (variations in curve morphology and magnitude, age of onset, rate of progression), and a prognosis ranging from increase in curve magnitude, to stabilization, or to resolution with growth. Genetic factors are known to play a role, as observed in twin studies and singleton multigenerational families [1].

A recent study of monozygotic and dizygotic twins from the Swedish twin registry estimated that overall genetic effects accounted for 38 % of the observed phenotypic variance, leaving the remaining 62 % to environmental influences [2]. Genetic complexity in IS is further inferred from inconsistent inheritance [3–6], discordance among monozygotic twins [7–9], and highly variable results from genetic studies.

Genetic variants that can affect a person’s predisposition to spinal curvature and the propensity for progression to severe curvature are still unknown. Since 1992, over 60 studies have attempted to identify genes by either genome-wide or hypothesis-driven designs, using either pedigrees (linkage analysis) or unrelated case–control population samples (association studies). Of over 30 candidate genes tested, 18 unique loci have been identified, suggesting that IS may be caused by multiple genes segregating differently in various populations. The goal of this review was to evaluate the various genetic studies and amalgamate their results to provide new insights. As reviewing genetic studies in a complex syndrome such as IS requires an evaluation of study design, and not merely a reporting of the findings [11], this comprehensive review may also serve as a guide for the design and interpretation of future genetic studies in IS [12].
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Connective tissue structure

To summarize, of the structural genes tested, TIMP2 was positively associated with thoracic curve severity in a Chinese cohort. These results need to be replicated using an independent cohort, especially as certain associations such as MATN1 or MMP3 were not replicated using larger cohorts. Furthermore, the linkage and transmission disequilibrium studies that showed negative results may have been underpowered to detect common variants possibly associated with IS, so those genes cannot be ruled out in the general population. Nonetheless, the study showing a negative association between the five lysyl oxidase genes and IS had 80 % power to detect an odds ratio of 1.7–2.0, assuming a dominant model of inheritance with no additive or multiplicative effects, a prevalence in the population of 3 %, and a minor allele frequency of 0.10 [24].

Bone formation and bone metabolism

To summarize, CALM1, IL6, LEP, and VDR seemed to be associated with curve predisposition, and IL6, VDR, and OPG with low bone mineral density. These associations need to be verified in larger cohorts. Furthermore, the negative studies described in this section had such small cohorts that we cannot rule out genetic associations for these candidates without further study.
Асимметричное изменение функции хондро-бластов в органе роста позвоночника – основного патогенетического признака ИС – предположи-тельно могло быть обусловлено нарушением ге-нетической регуляции функционирования кле-ток. Логично предположить, что асимметрия роста

Melatonin signaling pathway

To summarize, none of the melatonin pathway-associated genes seemed to be associated with IS. Although an association with MTNR1A, MTNR1B, and TPH1 was suggested by smaller studies, larger cohorts did not support their conclusions. These later studies were sufficiently powered to detect any potential effects had they been present.

Puberty and growth

To summarize, associations in small populations between common polymorphisms of the genes encoding the α- and β-estrogen receptors and IS were not confirmed in two larger studies. Another two studies found no association for GHR. Whether IGF1 or GPER are associated with IS needs to be confirmed in larger cohorts.


In this comprehensive review of the genetics underlying IS, we analyzed 50 studies. Findings involved genes related to connective tissue structure, bone formation/metabolism, melatonin signaling pathways, puberty and growth, and axon guidance pathways. The genetic basis for the etiology and prognosis of IS remains elusive, however. As with other genetic studies, the goals were to identify susceptibility genes for IS, define disease modifying genes, and explain why some curves progress to severity while others do not (genes that could be shared with the asymptomatic healthy population). The major difficulty faced by IS genetic studies is phenotypic and genetic heterogeneity. We found that IS genetic studies were overrepresented by underpowered studies that suggested an association, and then by underpowered replication studies that could not confirm or refute the original hypotheses. Although an increase in the number of individuals generally enhances the power of a study to detect an effect, genetic heterogeneity in complex diseases like IS is a major obstacle that cannot be overcome by such means alone.

With the advent of high-throughput technologies, future studies will be able to genotype a greater number of markers to possibly identify causal variants. However, understanding the difficulties surrounding this complex phenotype and the strengths and weaknesses of prior studies is crucial for progress in defining the genetics of this deformity. The use of biological endophenotypes such as those defined by Moreau et al. as well as restricted clinical definitions may facilitate the partitioning of variation and increase the power of detecting genetic associations. In addition, replication studies should use power analysis to minimize the possibility of false negatives. Further, when multiple polymorphisms are tested, an appropriate correction for significance thresholds needs to be applied.
Tags: Дисплазия, Фармакология

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