The document discusses adolescent idiopathic scoliosis (AIS) as a genetic disease characterized as a complex trait, emphasizing that different genetic factors influence its initiation and progression. It presents findings from various studies indicating high heritability rates and explores genetic predisposition, particularly the LBX1 gene. Despite advancements in genetic research on AIS, the clinical utility of these findings remains limited, as the effect sizes of genetic markers are small and environmental factors significantly impact disease severity.

1. 鄧亮生, CUHK
“AIS is a genetic disease, complex trait”
- How much we know after 2007
Nelson Tang, MD
The Chinese University of Hong Kong

2. 鄧亮生, CUHK
AIS as a Complex-traits Disease since 2007
• Back in 2007, AIS was called a complex trait
for the first time.
• My team published this review about the
possible etiology and pathogenesis of
idiopathic scoliosis (AIS)
• Two statements were made then (CORR,2017).
• 1. AIS is a genetic disease (complex trait)
• 2. Research of AIS needs to separately
investigate the initiation and progression
phases. These 2 phases are influenced by
different factors

3. 鄧亮生, CUHK
AIS as a Complex-trait genetic disease
• Systemic disease: not only spine affected
• Both Single gene & Polygenic inheritance
• Different mechanisms / genes for
INITIATION & PROGRESSION
1. AIS is a genetic disease (complex trait)

4. 鄧亮生, CUHK
Onset of AIS
Curve Progression & Severity
Normal puberty
Environmental
factors
Disease modifier genes/
progression genes
Affects progression & severity of
curve
e.g. ESR, COL, IGF1 ….
Initiation Phase:
Progression
Predisposition genes/
initiation genes
(More than ONE gene)
Family Linkage Studies
(Miller et al.)
Association Studies
(e.g. Melatonin receptor)
2. To separately investigate
the initiation and
progression phases

5. 鄧亮生, CUHK
We have come a long way
2000 2005/06
1. Polygenetic disease: Population studies
2. Initiation vs progression genes
3. Axial Biotech
4. Candidate Gene studies
GWAS became
feasible
(WTCCC 2007)
2007
Dr. Cotrel’s
China Visit
2010
TDT
2011
Case control
GWAS found
LBX1
(Ikegawa)
Familial Study
Only

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Old genetic diseases
Genetics
Environment
Disease
New genetic diseases (complex trait)
复杂性状
BRCA1
Mutation
4%
No
mutation
96%
Effect size
(penetrance)

7. 鄧亮生, CUHK
Architecture of
Genetics in Complex trait
• 1. How many Genes ?
• 2. How big the effect ?
• 3. Any clinical Use ?
• The idea have been presented in
Cotrel’s meeting in Institut de
France, SRS, and other orthopedic
meetings etc

8. 鄧亮生, CUHK
How much caused by Genetics ?
• Tang NL, Yeung HY, Hung VW, et al. Genetic epidemiology and heritability
of AIS: A study of 415 Chinese female patients. J Orthop Res.
2012;30(9):1464-1469. doi:10.1002/jor.22090
• Out of the total 531 sibs of AIS cases, 94 sibs had scoliosis (sibling
recurrence risk = 17.7%). The prevalence of AIS among male and female
sibs of an index case were 11.5% (95% CI = 7.5-15.5) and 23.0% (95% CI
= 18.1-27.9), respectively. Female sibs of an index case had an increased
risk of 8.9-fold (95% CI = 3.2-34.4) for developing AIS. These recurrent
risks were significantly higher than the risk in the control group (p <
0.0001). Overall, heritability was estimated to be 87.5 ± 11.1%.

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Heritability
• Overall heritability: 98±5% (h2±S.E.)
• Female: 95±7%
• J Orth Research 2012

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Medical Condition Heritability
Eye color 0.98
AIS 0.98
Hair curliness 0.95
Autism 0.9
Epilepsy 0.88
Type-1 diabetes 0.88
Celiac disease 0.87
Height 0.81
Schizophrenia 0.81
Alzheimer's disease 0.79
Polycystic ovary
syndrome
0.72
Bipolar disorder 0.7
Menarche, age at 0.7

11. 鄧亮生, CUHK
Initiation of AIS is a genetic
disease (complex trait)
• Hypothesis:
– Initiation of AIS is a genetic disease (complex
trait)
• Prediction:
– Genome wide association study will disclose
the genetic predisposition for initiation of
curve (initiation phase)
• Action:
– Time to do GWAS

13. 鄧亮生, CUHK

14. 鄧亮生, CUHK
S-2000
Scoliosis 2000 proposal

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Genotyping Platforms
• 2 common platforms
• Affymetrix: ver 6, >1M SNPs
• Illumina: chips with various
density
李嘉誠健康科學研究所

16. 鄧亮生, CUHK
GWAS worked and found LBX1
• So far, LBX1 is the only AIS predisposition
gene that can be replicated (confirmed) by
other research groups.
• That is It is REAL.
Joint Scoliosis Research
Centre CUHK NU

17. 鄧亮生, CUHK
Joint Scoliosis Research
Centre CUHK NU
The idea that
AIS is a genetic
disease (complex trait)
is first proven

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However,
• Like other variants found by GWAS
• The risk effect is small (Odd ratio of < 2).

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What we can learn from
GWAS study of Height ?
• Styrkarsdottir, U., Stefansson, O. A., Gunnarsdottir, K., …..Nelson Tang…..et al. (2019). GWAS of bone size yields
twelve loci that also affect height, BMD, osteoarthritis or fractures. Nature Communications, 10(1), 2054.
https://doi.org/10.1038/s41467-019-09860-0
• Also reviewed by Chatterjee et al 2013.
Joint Scoliosis Research
Centre CUHK NU

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Joint Scoliosis Research
Centre CUHK NU

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Low hanging
fruit is found
first among
others

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Missing Heritability
• Heritability : >90% (sib risk: ~10x)
• LBX1, odd ratio = 1.8x, MAF=0.5
• Attributable risk due to LBX1: 15%

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How Many Genes ?
• Many More involved
• Need large sample size to find
http://www.nature.com/nature/journal/v467/n7317/fig_tab/nature09410_F1.html

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The first Chinese AIS GWAS 2015
• Zhu Z, Tang NL, Xu L, et al. Genome-wide association study identifies
new susceptibility loci for adolescent idiopathic scoliosis in Chinese
girls. Nat Commun. 2015;6:8355. doi:10.1038/ncomms9355
• Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215,
Pcombined=2.95 × 10(-9)), 2q36.1 between PAX3 and EPHA4 (rs13398147,
Pcombined=7.59 × 10(-13)) and 18q21.33 near BCL-2 (rs4940576, Pcombined=2.22 ×
10(-12)). In addition, we refine a previously reported region associated with AIS at
10q24.32 (rs678741, Pcombined=9.68 × 10(-37)), which suggests LBX1AS1, encoding
an antisense transcript of LBX1, might be a functional variant of AIS. This is the first
GWAS investigating genetic variants associated with AIS in Chinese population, and the
findings provide new insight into the multiple aetiological mechanisms of AIS.

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How Big the effect ?
• Each SNPs has small O.R.
• OR 1.3 to 1.5
• Little immediate clinical utility

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Is it useful in clinic ?
• Not directly
• Clinical
parameters
would perform
better

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Scolioscore ?
• 53 SNPs to predict progression
• You may remember my comment from
Day 1 that disease progression could not
be predicted by genetic markers (for the
great majority of AIS patients)

28. 鄧亮生, CUHK
Joint Scoliosis Research
Centre CUHK NU
Severity of curve, Cobb angle:
UNLIKELY to be under large genetic influence
e.g. TWINs with very different severity
So, CLINICAL and ENVIRONMENTAL factors will be better predictor

29. 鄧亮生, CUHK
Joint Scoliosis Research
Centre CUHK NU