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Heritability of spinal pain and consequences of spinal painA comprehensive genetic epidemiologic analysis using a population-based sample of 15328 twins ages 2071 years.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 61, No. 10, October 15, 2009, pp 1343–1351
DOI 10.1002/art.24607
© 2009, American College of Rheumatology
SPECIAL ARTICLE: EPIDEMIOLOGY OF THE RHEUMATIC DISEASES
Heritability of Spinal Pain and Consequences of
Spinal Pain: A Comprehensive Genetic
Epidemiologic Analysis Using a Population-Based
Sample of 15,328 Twins Ages 20 –71 Years
JAN HARTVIGSEN,1 JAN NIELSEN,2 KIRSTEN OHM KYVIK,2 RENE FEJER,3 WERNER VACH,2
IVAN IACHINE,2 AND CHARLOTTE LEBOEUF-YDE4
Objective. To assess the relative contribution of genetic and environmental factors to different definitions of spinal pain
and consequences of spinal pain.
Methods. The Danish Twin Registry contains detailed survey information on spinal pain and its consequences in twins
ages 20 –71 years. A classic genetic epidemiologic analysis was performed in order to establish heritability for a number
of phenotypes, including location of pain, radiation of pain in the extremities or chest, pain duration, and combinations
of pain in >1 spinal area. Consequences included reduced physical activity, sick leave, care seeking, change of work, and
disability pension. The analysis included a biometric analysis based on the effect of shared genetic and common
environmental factors. Furthermore, a bivariate twin model was fitted to identify genetic and environmental correlations.
Results. Altogether, data on 15,328 twin individuals (44% monozygotic and 56% dizygotic) from complete twin pairs
were included. Genetic susceptibility explained ⬃38% of lumbar pain, 32% of thoracic pain, and 39% of neck pain. For
patterns of pain, estimates were 7% for lumbar/thoracic, 24% for lumbar/cervical, 0% for thoracic/cervical, and 35% for
pain in all 3 areas. Moderate to high genetic correlations indicated a common genetic basis for many spinal pain
syndromes. In general, heritability was higher for women, and only a minor age effect was seen.
Conclusion. Heritability estimates for pain in different spinal regions are quite similar and there is a moderate to high genetic
correlation between the phenotypes. This may indicate a common genetic basis for a high proportion of spinal pain.
INTRODUCTION
Spinal pain and its consequences have developed into a
modern epidemic. Unfortunately, effects of efforts to preData collection was supported by the Danish Foundation
for Chiropractic Research and Postgraduate Education.
1
Jan Hartvigsen, DC, PhD: Clinical Locomotion Science,
University of Southern Denmark, Campusvej 55, 5230
Odense M, and Nordic Institute of Chiropractic and Clinical
Biomechanics, Clinical Locomotion Science, Forskerparken
10A, 5230 Odense M, Denmark; 2Jan Nielsen, MSc, Kirsten
Ohm Kyvik, MD, PhD, Werner Vach, PhD, Ivan Iachine,
PhD: University of Southern Denmark, JB Winsløwsvej 9A,
5000 Odense C, Denmark; 3Rene Fejer, DC, PhD: Clinical
Locomotion Science, University of Southern Denmark,
Campusvej 55, 5230 Odense M, Denmark; 4Charlotte
Leboeuf-Yde, DC, PhD: Back Research Center, Clinical Locomotion Science, Lindevej 5, 5750 Ringe, and University of
Southern Denmark, Odense, Denmark.
Address correspondence to Jan Hartvigsen, DC, PhD, Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Campusvej 55, DK-5230 Odense
M, Denmark. E-mail: jhartvigsen@health.sdu.dk.
Submitted for publication January 14, 2009; accepted in
revised form April 3, 2009.
vent and treat the various manifestations have proven to be
of modest benefit, at least in a public health perspective
(1–3). This is probably because the underlying mechanisms behind spinal pain and its consequences are poorly
understood, making it difficult to tailor specific interventions on a rational basis. Recently, however, 2 promising
directions have emerged.
First and foremost, it is becoming increasingly clear
from population studies that the various forms of spinal
pain, i.e., low back pain, mid-back pain, and/or neck pain,
are probably not separate and site-specific entities, but
rather in many cases part of a more general musculoskeletal pain syndrome (4 – 6) and maybe even an indicator of
poor general health (7,8). Of course, this line of thinking
has implications for both researchers and clinicians, because pain reported in a localized spinal area may be both
a result of local tissue injury and an expression of a general
musculoskeletal frailty syndrome (9).
Second, there is now convincing evidence that genetic
susceptibility plays a significant role in many aspects of
spinal pain and pathology, including reporting of low back
pain at all ages (10 –13), reporting of neck pain (14), cer1343
1344
vical and lumbar disc degeneration observed on magnetic
resonance imaging (MRI) (12,15), and lumbar osteophyte
formation (16). Results of a recent study using a small but
population-based twin sample indicated that up to 25% of
genetic influences on back pain history were due to the
same genetic influences that affected disc height narrowing, the degenerative finding most associated with back
symptoms in the study sample (12). Furthermore, there is
now convincing evidence that disc degeneration may be
primarily caused by genetic influences and not, as once
believed, primarily by aging and wear and tear (17). This
may in part explain why interventions aimed at modifying
environmental factors such as reduced workload have not
resulted in less back pain in the population. Interestingly,
there is also emerging evidence that the documented association between back and neck pain and depression (18 –
20) may be primarily due to common genetic effects between the two (21). Therefore, it is tempting to speculate
that the pattern of co-occurrence of musculoskeletal and
other symptoms observed in population studies may to a
significant extent be genetically based.
One approach to this question would be to study patterns of heritability and genetic correlation between different phenotypes of spinal pain in the same population.
Such research requires very large samples of twins, and
the Danish Twin Registry, the world’s largest and oldest
twin registry with information on more than 120 birth
cohorts of twins (22), is well suited for such a purpose. In
2002, an extensive survey of all Danish twins born between 1931 and 1982 including information on pain in the
3 spinal areas (neck, mid back, and low back) and consequences of such pain was performed. Details of the prevalence and patterns of findings in an epidemiologic perspective have been reported elsewhere (4). We
subsequently performed a comprehensive genetic epidemiologic analysis in order to answer the following research questions: 1) What is the relative genetic and environmental contribution to different phenotypes, i.e.,
different definitions of spinal pain and consequences of
spinal pain?, 2) Is there a common pattern in the heritability estimates for spinal pain and its consequences between the spinal regions?, and 3) Can we identify correlations between the genetic and environmental factors
influencing the region-specific phenotypes?
PATIENTS AND METHODS
Participants. The Danish Twin Registry covers birth cohorts from 1870 to 2001 (22). It is among the largest and
most comprehensive twin registries in the world, and is
considered representative of the Danish general population (23). In April 2002, all twins born between 1931 and
1982 and registered in the Danish Twin Registry who had
previously agreed to participate in research received a
20-page questionnaire booklet containing questions on a
wide variety of health-, work-, and lifestyle-related factors.
The information letter stated the purpose of the projects as
focusing on the twins’ health in general. The questionnaire
was followed by one reminder, which is the number of
reminders allowed by the Danish Scientific Ethical Com-
Hartvigsen et al
mittees. The study was approved by the Regional Scientific Ethics Committee and the Danish Data Protection
Agency.
Zygosity of the twin pairs was determined using answers to questions regarding resemblance between twins
in a pair. This method has been shown to yield correct
classification in 97% of patients within this cohort (23).
Variables. Information regarding spinal pain (neck
pain, mid-back pain, and low back pain) was collected
using the Standardized Nordic Questionnaire. This questionnaire has been validated for both test–retest reliability
and validity (24 –26).
Phenotypes of pain in the different spinal regions (low
back pain, mid-back pain, and neck pain) included pain in
the past year and the number of days with pain in the past
year (later categorized into 1–30 days and ⬎30 days out of
the past year). In addition, we studied those reporting
different pain patterns, i.e., low back pain and mid-back
pain but no neck pain, low back pain and neck pain but no
mid-back pain, mid-back pain and neck pain but no low
back pain, and low back pain, mid-back pain, and neck
pain, as well as the 3 patterns of occurrence of pain in one
specific region alone, in order to see if heritability for
specific regional pain differed from pain in more than 1
region. Finally, pain reported as radiating from the lumbar,
thoracic, and cervical areas was included, described as
pain in the leg(s), chest, and arm(s), respectively. All variables relate to symptoms in the past year.
Phenotypes of consequences of spinal pain during the
past year included 1) reduced physical activity in the past
year, 2) sick leave during the past year, 3) sought care
during the past year, 4) changed work or tasks at work
during the past year, and 5) disability pension (including
being under consideration for disability pension and already having a disability pension). It is relevant to note
that there are no financial barriers to access the Danish
health care system and that sick leave and compensation
are available regardless of the cause of the disease. The
work-related variables were only applied to actively working individuals. Additional variables were sex and age
groups (20 –35, 36 –50, and 51–71 years).
Statistical analysis. The analysis was stratified by sex,
therefore limiting the analysis to same-sex twin pairs. Participants were then divided into 3 age groups (20 –35,
36 –50, and 51–71 years) (14). Accordingly for each variable, heritability estimates for the different phenotypes
were obtained for men and women and each of the age
groups separately.
Heritability estimates were obtained using a classic biometric analysis based on the assumption that the total
phenotypic variance in a trait can be partitioned into components attributable to genetic and environmental effects
(27). In the univariate variance component model, one
assumes that the phenotypic variance can be partitioned
into an additive genetic component (A), a dominant genetic component (D), a shared environmental component
(C), and a nonshared environmental component (E) (27). In
all previous analyses of back and neck pain data from the
Comprehensive Genetic Epidemiologic Analysis of Spinal Pain
Danish Twin Registry using this and other cohorts
(3,11,14,28), the AE biometric submodel showed the best
fit to the data, and therefore we chose to fit only that
model. This ensured comparability of estimates inside the
analysis and with other analyses.
To understand the genetic and environmental contribution to the association between the 3 region-specific phenotypes, we further fitted a bivariate heritability twin
model (29). From this model, we obtained estimates of the
correlation between genetic and environmental factors influencing the single phenotypes. A high genetic/environmental correlation indicates that the phenotype is influenced by the same genetic/environmental factors. We also
report bivariate heritabilities expressing to what degree the
overall association between the 2 phenotypes can be attributed to correlations of genetic or environmental factors. The Mx software package was used for all biometric
modeling (30).
RESULTS
Of 46,818 questionnaires sent out, 34,902 (74.5%) were
returned immediately or after the first reminder and regarded as valid. In this analysis, only twin pairs where
both twin individuals had provided valid answers were
included, and because analyses were performed separately
for men and women, opposite-sex dizygotic pairs were
excluded, as were twins without zygosity determination,
triplets, and quadruplets. This resulted in a final sample of
15,328 twin individuals (6,412 men and 8,916 women)
comprising 7,664 complete twin pairs, of which 3,402
were monozygotic and 4,262 were dizygotic. Further details regarding the sample and prevalence of the various
phenotypes have been reported in detail elsewhere (4).
The prevalences of phenotypes included in this analysis
for monozygotic and dizygotic twins are shown in Table 1.
No statistical differences beyond chance were found between the 2 zygosities.
Heritability estimates based in the univariate AE model
estimating the overall genetic and environmental effect on
the different phenotypes are shown in Figures 1, 2, and 3.
For spinal pain in the 3 spinal regions, genetic susceptibility explained 38% (95% confidence interval [95% CI]
33– 42) of low back pain, 32% (95% CI 26 –39) of mid-back
pain, and 39% (95% CI 34 – 43) of neck pain (Figure 1). If
this was defined as pain in one region only, i.e., low back
pain, mid-back pain, or neck pain alone with no pain
reported in the other regions, the estimates were 21%
(95% CI 14 –27) for low back pain only, 15% (95% CI
0 – 42) for mid-back pain only, and 18% (95% CI 9 –28) for
neck pain only. For radiating pain in the leg, chest, and
arms, genetic factors explained 31% (95% CI 26 –37), 40%
(95% CI 30 –50), and 35% (95% CI 29 – 41), respectively.
For practically all of the phenotypes, the heritability estimates for women were higher than for men, although this
was not statistically significant. When these phenotypes
were broken down into age strata (Figure 1), no clear age
effect was seen for low back pain or sciatica; for mid-back
pain and pain radiating into the chest this was also the
case, although low prevalences in the age strata resulted in
1345
wide confidence intervals. For neck pain and mid-back
pain and for pain radiating into the upper extremity or
chest, there was a tendency of lower heritability with age
for men and stable or slightly increasing estimates for
women.
For the different pain patterns (Figure 2), the overall
heritability estimates were 7% (95% CI 7–32) for low back
pain and mid-back pain but no neck pain, 24% (95% CI
16 –31) for low back pain and neck pain but no mid-back
pain, 0% (95% CI 0 –34) for mid-back pain and neck pain
but no low back pain, and 35% (95% CI 27– 43) for low
back pain, mid-back pain, and neck pain. In spite of wide
confidence intervals, there was a clear tendency for higher
heritability in women for all of the phenotypes (Figure 2).
Furthermore, women showed increasing heritability with
age, whereas the opposite was the case for men.
For consequences of spinal pain, the results are shown
in Figure 3. Overall, heritability estimates for consequences are quite similar between the spinal regions. The
highest heritability was found for the most severe consequence, early pension. There are only minor differences
between men and women, although estimates for early
pension were consistently higher for men.
Genetic, environmental, and phenotypic correlations
and bivariate heritability estimates are shown in Table 2.
For both men and women, genetic correlations between
low back pain, mid-back pain, and neck pain were moderate to high regardless of age, and the bivariate heritability estimates were roughly equal to the univariate estimates, indicating that genetic factors are as important in
explaining the pain pattern phenotypes as they are in
explaining the region-specific phenotypes.
DISCUSSION
In a comprehensive genetic epidemiologic analysis using
survey data from a large population-based twin cohort, we
have shown that spinal pain and its consequences are to a
significant extent determined by genetic factors for both
men and women throughout adulthood. Furthermore, the
size of the genetic contribution to spinal pain is remarkably similar between the 3 spinal regions. We even found
strong genetic correlations between all 3 regions for all of
the age groups, indicating that to a large extent, the same
genes are responsible for the pain regardless of the location. The fact that the bivariate heritability estimates were
of the same magnitude as the univariate estimates further
supports the conclusion that genetic factors are important
in explaining and understanding the interplay between
pain in the various regions of the spine.
We found that genetic influences on pain patterns involving 2 regions were consistently lower than for pain
involving any specific region alone. This indicates that
genetic predisposition to pain in more than one spinal
region is probably not very common. In a recently published PhD thesis, Nyman concluded quite the opposite,
namely that heritability estimates nearly doubled (from
⬃30% to 60%) when low back pain and neck pain were
considered together instead of separately (31). Although a
population-based sample of twins was used in this Swed-
1346
Hartvigsen et al
Table 1. Prevalence of included phenotypes in 15,328 Danish twins ages 20 –71 years*
Age 20–35 years
Phenotype
Men, no.
Women, no.
Total, no.
LBP in the past 12 months
Men
Any pain
1–30 days
⬎30 days
Sciatica
Women
Any pain
1–30 days
⬎30 days
Sciatica
MBP in the past 12 months
Men
Any pain
1–30 days
⬎30 days
Sciatica
Women
Any pain
1–30 days
⬎30 days
Sciatica
NP in the past 12 months
Men
Any pain
1–30 days
⬎30 days
Sciatica
Women
Any pain
1–30 days
⬎30 days
Sciatica
Pain in ⬎1 area
Men
LBP ⫹ MBP
LBP ⫹ NP
MBP ⫹ NP
LBP ⫹ MBP ⫹ NP
Women
LBP ⫹ MBP
LBP ⫹ NP
MBP ⫹ NP
LBP ⫹ MBP ⫹ NP
Consequences of LBP
Men
Reduced physical activity
Sought care
Change work duty
Sick leave
Early pension
Women
Reduced physical activity
Sought care
Change work duty
Sick leave
Early pension
MZ
DZ
1,453
2,092
3,545
1,587
1,914
3,501
Age 36–50 years
P†
MZ
DZ
1,298
1,550
2,848
2,037
2,299
4,336
Age 51–71 years
P†
MZ
DZ
1,220
1,380
2,600
2,461
2,562
5,023
P†
36.0
29.1
7.5
10.2
39.0
30.9
8.5
13.3
0.108
0.285
0.311
0.011
49.3
38.2
11.6
24.0
45.6
35.7
10.5
23.6
0.048
0.162
0.363
0.766
38.8
28.6
10.5
21.3
36.8
24.6
11.6
22.2
0.258
0.014
0.379
0.547
41.7
30.9
11.1
15.3
44.0
32.1
12.5
16.0
0.175
0.462
0.191
0.594
50.3
35.9
15.3
27.2
51.2
35.2
17.1
26.9
0.637
0.670
0.166
0.816
41.4
23.6
16.1
27.5
40.8
22.5
16.3
26.5
0.770
0.468
0.888
0.565
14.9
12.4
2.7
4.4
15.3
12.3
3.5
4.6
0.785
0.939
0.246
0.806
12.1
9.8
3.7
4.5
10.5
9.1
2.2
3.4
0.159
0.477
0.024
0.113
6.6
4.6
2.3
3.7
7.0
4.1
2.7
4.7
0.683
0.528
0.492
0.172
15.8
11.6
4.6
4.4
15.7
11.4
4.8
4.5
0.994
0.866
0.737
0.816
17.8
13.6
5.6
7.3
17.9
13.1
6.5
6.8
0.926
0.653
0.296
0.529
10.4
5.3
6.2
5.7
12.1
6.1
6.0
7.1
0.126
0.388
0.839
0.129
23.1
18.6
4.8
6.9
25.6
20.6
5.9
7.4
0.126
0.194
0.229
0.614
31.3
24.3
9.1
12.8
27.9
22.4
7.4
11.9
0.039
0.246
0.112
0.451
21.0
14.9
8.1
11.9
22.4
14.9
8.4
12.2
0.350
0.959
0.825
0.837
35.2
24.5
11.4
12.6
37.1
25.6
12.4
13.5
0.242
0.434
0.362
0.414
47.1
32.3
16.3
25.2
46.4
30.9
17.7
25.0
0.713
0.387
0.316
0.903
33.9
17.4
16.0
23.4
34.0
17.7
15.6
22.4
0.955
0.875
0.788
0.545
2.7
7.4
1.7
6.3
2.7
8.7
1.4
6.9
0.966
0.189
0.650
0.520
1.8
11.8
0.8
7.7
1.8
10.6
0.8
5.4
0.992
0.277
0.840
0.008
1.1
7.5
0.6
2.9
1.0
7.4
0.2
3.5
0.625
0.945
0.123
0.286
1.8
11.0
1.4
9.9
1.9
13.1
1.2
9.6
0.787
0.047
0.518
0.699
1.3
15.3
1.2
13.0
1.9
15.1
1.3
11.8
0.164
0.871
0.829
0.316
0.7
8.4
0.6
5.9
0.7
7.7
0.8
6.8
0.854
0.441
0.480
0.256
12.1
12.2
5.1
8.6
0.4
12.0
13.6
5.8
11.1
0.7
0.905
0.263
0.454
0.066
0.307
21.2
18.5
8.7
12.4
1.5
18.9
17.6
8.1
12.4
1.3
0.120
0.503
0.537
0.955
0.746
17.2
14.4
6.2
7.7
2.4
17.5
15.0
7.6
8.6
3.9
0.839
0.669
0.122
0.436
0.027
11.4
13.1
6.3
6.8
0.6
12.6
14.5
6.2
8.4
0.9
0.283
0.202
0.820
0.143
0.218
18.7
20.6
9.0
9.4
1.9
19.6
20.6
10.7
11.1
2.8
0.514
0.999
0.101
0.135
0.086
18.3
19.8
8.3
11.4
4.9
19.1
0.536
20.0
0.881
8.0
0.683
10.0
0.325
5.1
0.779
(continued)
Comprehensive Genetic Epidemiologic Analysis of Spinal Pain
1347
Table 1. (Cont’d)
Age 20–35 years
Phenotype
Consequences of MBP
Men
Reduced physical activity
Sought care
Change work duty
Sick leave
Early pension
Women
Reduced physical activity
Sought care
Change work duty
Sick leave
Early pension
Consequences of NP
Men
Reduced physical activity
Sought care
Change work duty
Sick leave
Early pension
Women
Reduced physical activity
Sought care
Change work duty
Sick leave
Early pension
Age 36–50 years
Age 51–71 years
MZ
DZ
P†
MZ
DZ
P†
MZ
DZ
P†
3.9
4.6
1.7
3.9
0.1
5.0
4.9
1.9
3.2
0.3
0.182
0.699
0.620
0.402
0.322
4.1
4.3
1.7
2.2
0.2
2.7
4.4
1.3
1.7
0.2
0.025
0.871
0.402
0.344
0.931
2.2
2.9
0.5
1.3
0.8
3.0
3.1
1.2
1.3
1.0
0.187
0.665
0.042
0.894
0.591
3.2
5.5
1.9
1.6
0.2
3.9
6.1
2.3
2.5
0.5
0.218
0.437
0.394
0.125
0.222
4.5
7.9
2.9
2.2
0.6
4.4
7.3
2.7
2.2
1.0
0.934
0.507
0.799
0.954
0.298
4.5
5.6
2.0
2.7
1.4
5.2
6.0
2.2
3.2
1.7
0.411
0.670
0.644
0.497
0.529
5.5
8.0
1.6
4.2
0.1
5.3
8.1
2.3
4.5
0.3
0.858
0.888
0.187
0.792
0.485
8.4
10.5
3.5
3.8
0.7
6.7
9.8
2.6
3.8
0.5
0.067
0.538
0.163
0.953
0.582
5.3
7.6
1.9
3.3
1.1
7.6
9.3
2.5
2.6
1.7
0.009
0.089
0.287
0.348
0.158
6.9
12.7
3.3
5.0
0.4
8.7
14.2
3.5
7.0
0.7
0.036
0.206
0.721
0.055
0.210
14.3
20.7
6.6
8.3
1.3
12.8
21.5
6.1
7.1
1.8
0.187
0.597
0.571
0.243
0.269
12.8
16.2
5.2
5.0
3.8
11.7
17.3
5.4
6.4
3.5
0.307
0.402
0.801
0.211
0.595
* Prevalences are the percentage for all categories for monozygotic (MZ) and dizygotic (DZ) twins separately unless otherwise indicated. LBP ⫽ low
back pain; MBP ⫽ mid-back pain; NP ⫽ neck pain.
† Test for equality.
Figure 1. Relative influences of genetic and environmental components in liability to low
back pain, mid-back pain, and neck pain during the past year for Danish men and women
ages 20 –71 years.
1348
Hartvigsen et al
Figure 2. Relative influences of genetic and environmental components in liability to pain
in multiple spinal areas during the past year for Danish men and women ages 20 –71 years.
LBP ⫽ low back pain; MBP ⫽ mid-back pain; NP ⫽ neck pain.
ish study, participation rates were lower and the definitions of the phenotypes were different from ours. It is
unclear whether these factors explain this apparent paradoxical finding, but it emphasizes that heritability estimates are likely to differ for different definitions of spinal
pain.
When considering consequences of spinal pain, the
more severe and costly consequences such as early pension demonstrate the highest heritability. However, early
pension is not solely related to structural pathology or
even to pain, but reflects a complex phenotype in the
border area between physiology, psychology, and sociology, all 3 of which have shown strong genetic influences
(29,32). In other words, new and even more comprehensive analyses including phenotype definitions comprising
extensive spinal pain information (such as in this study)
combined with clinical information (12,33) and psychosocial information (21) are needed to unravel the genetic
basis for complex biopsychosocial phenomena like spinal
pain.
In general, regardless of subgroup, heritability estimates
for spinal pain in women were higher than for men, although most confidence intervals were overlapping. There
have been conflicting conclusions from previous twin
studies regarding sex differences in heritability; however,
overlapping confidence intervals between the sex-specific
estimates and different definitions of back and neck pain,
i.e., different phenotypes, have hampered interpretability
(11–14,28). Our results raise the question of whether this
consistent difference is due to a sex-specific genetic influence. Fejer et al examined this heterogeneity in relation to
lifetime prevalence of neck pain using so-called sex-limitation models, and found that sex differences in the heritability of neck pain were not due to any sex-specific
genetic influence (34). Rather, they (also) proposed that
neck pain (and probably spinal pain in general) is a com-
Figure 3. Relative influences of genetic and environmental components in liability to
consequences of spinal pain during the past year for Danish men and women ages 20 –71
years.
Comprehensive Genetic Epidemiologic Analysis of Spinal Pain
1349
Table 2. Genetic, environmental, and phenotypic correlations and bivariate heritability between pain in different spinal areas
during the past year for 15,328 Danish twins ages 20 –71 years*
Phenotype
LBP ⫹ MBP
Men, years of age
20–35
36–50
51–71
Women, years of age
20–35
36–50
51–71
LBP ⫹ NP
Men, years of age
20–35
36–50
51–71
Women, years of age
20–35
36–50
51–71
MBP ⫹ NP
Men, years of age
20–35
36–50
51–71
Women, years of age
20–35
36–50
51–71
Genetic
correlation
(95% CI)
Environmental
correlation
(95% CI)
Phenotypic
correlation
(95% CI)
Bivariate
heritability
(95% CI)
0.54 (0.25–0.85)
1.00 (0.41–1.00)
1.00 (0.30–1.00)
0.41 (0.26–0.55)
0.37 (0.24–0.50)
0.49 (0.34–0.64)
0.45 (0.39–0.51)
0.46 (0.40–0.52)
0.54 (0.48–0.60)
0.39 (0.16–0.62)
0.36 (0.11–0.59)
0.30 (0.05–0.55)
0.74 (0.57–0.93)
0.79 (0.55–1.00)
0.66 (0.45–0.89)
0.50 (0.38–0.61)
0.52 (0.39–0.64)
0.54 (0.39–0.68)
0.59 (0.55–0.63)
0.61 (0.56–0.65)
0.59 (0.54–0.64)
0.47 (0.34–0.60)
0.43 (0.28–0.58)
0.45 (0.28–0.62)
0.62 (0.40–0.84)
0.86 (0.51–1.00)
0.54 (0.14–0.99)
0.47 (0.34–0.59)
0.35 (0.23–0.47)
0.60 (0.48–0.70)
0.52 (0.47–0.57)
0.47 (0.42–0.51)
0.57 (0.53–0.61)
0.42 (0.24–0.59)
0.44 (0.24–0.63)
0.24 (0.04–0.42)
0.75 (0.61–0.89)
0.64 (0.47–0.80)
0.74 (0.58–0.90)
0.46 (0.36–0.55)
0.49 (0.39–0.59)
0.53 (0.42–0.63)
0.57 (0.53–0.61)
0.55 (0.51–0.58)
0.61 (0.57–0.65)
0.51 (0.39–0.63)
0.45 (0.37–0.56)
0.47 (0.34–0.60)
0.69 (0.43–0.98)
0.76 (0.00–1.00)
1.00 (0.34–1.00)
0.52 (0.37–0.65)
0.54 (0.42–0.67)
0.53 (0.41–0.65)
0.58 (0.52–0.63)
0.54 (0.49–0.60)
0.60 (0.54–0.66)
0.41 (0.21–0.59)
0.11 (0.00–0.34)
0.26 (0.02–0.50)
0.73 (0.56–0.91)
0.72 (0.49–1.00)
0.84 (0.65–1.00)
0.54 (0.42–0.64)
0.57 (0.44–0.69)
0.58 (0.43–0.71)
0.61 (0.57–0.65)
0.62 (0.57–0.66)
0.68 (0.64–0.73)
0.46 (0.33–0.59)
0.39 (0.24–0.54)
0.50 (0.35–0.64)
* 95% CI ⫽ 95% confidence interval; LBP ⫽ low back pain; MBP ⫽ mid-back pain; NP ⫽ neck pain.
plex phenomenon with great psychological and social influences, which in turn has been shown to influence genetic liability to neck pain (33,34).
We found a negligible overall effect of age on the various
heritability estimates. Previously, conflicting results regarding the influence of age have been shown, and using a
different cohort of the Danish Twin Registry (The Longitudinal Study of Aging Danish Twins) and different definitions of back and neck pain, we found a strong environmental (and thus small genetic) influence in back and neck
pain in persons age ⬎70 years (13,28). Therefore, an association between age and heritability estimates is not apparent in comparisons between studies (12), although
Hestbaek et al found that common environment was most
important in relation to back pain in very young patients
(11). Given that physical and psychosocial exposures suspected of being risk factors for spine pain vary widely over
a lifetime, this lack of association may indicate a substantial interaction between genes and environmental exposures. Therefore, the value of estimating heritability from
twins is in establishing the likely success of specific strategies to detect the action of individual genes under the
influence of a range of environmental factors (33).
Several twin studies have dealt with the relationship
between the heritability of both cervical and lumbar disc
degeneration and back and neck pain (15,17,33). Collectively, an important genetic influence on degeneration has
been found, explaining as much as 75% of the underlying
disposition to disc degeneration (15), and Battié et al recently concluded that a substantial minority (23%) of the
genetic influence on pain was due to the same genetic
influences affecting disc degeneration (12). In other words,
disc degeneration is one pathway through which genes
may influence back pain, and rather than aging and wear
and tear, genetic influences appear to be responsible for
the larger part of disc degeneration (17). We did not have
access to MRI and our results are based entirely on survey
data. Therefore, we cannot investigate possible pathways
between imaging and pain. Nevertheless, as attractive as
imaging and hard data may seem, these are not necessarily
the best predictors of prognosis in patients with back pain
(35), whereas patient reporting has been found to be of
substantial value (36,37). We therefore believe that our
phenotypes are good, clinically relevant, and easy to relate
to, for example, primary care clinicians. It is important,
however, to remember that heritability estimates are dependent on both phenotype time and place. Therefore, the
estimates presented here cannot be directly applied to
other definitions of spinal pain, to future generations, or to
persons in other cultures (38).
Heritability estimates based on genetic epidemiologic
analyses are vulnerable to a number of factors and should
be interpreted with caution. Our estimates are most likely
too conservative because nondifferential misclassification,
1350
Hartvigsen et al
which is likely to happen in large questionnaire-based
surveys, will tend to lower the heritability estimates (39).
Furthermore, dissimilar twin pairs, which are most often
dizygotic, are less likely to participate in twin studies,
resulting in increased dizygotic correlations and therefore
again conservative heritability estimates (40). On the other
hand, if disease concordant pairs were more likely to participate than disease discordant pairs, heritability would
be biased upward (39). However, this is less of a problem
in large population-based samples such as this, but more
likely to bias studies based on volunteers responding to
media campaigns or studies based on twins who are seeking care for a particular condition.
The major strength of the current analysis is the large
and representative population-based sample (22). However, the results cannot be applied directly to the clinical
setting, and a comprehensive analysis involving several
subgroups with varying prevalence many times results in
thin strata and consequently imprecise estimates, even in
conditions as common as back and neck pain. Furthermore, we lack analyses including information on genetic
and environmental factors in spinal pain, comorbidities,
clinical tests, psychosocial factors, and risk factors from
life history. Including such information would allow us to
paint a comprehensive picture of the interplay between
genetic and environmental factors and to assess the genetic
correlations among all of these factors. Such an approach
would have the potential to correlate candidate genes to
clusters of relevant variables showing genetic correlations.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved the final version to be published. Dr. Hartvigsen had full
access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Study conception and design. Hartvigsen, Nielsen, Kyvik, Fejer,
Vach, Iachine, Leboeuf-Yde.
Acquisition of data. Hartvigsen, Kyvik, Fejer, Iachine, LeboeufYde.
Analysis and interpretation of data. Hartvigsen, Nielsen, Kyvik,
Fejer, Vach, Iachine, Leboeuf-Yde.
ACKNOWLEDGMENT
We gratefully acknowledge Professor Tom Bendix, DrMedSci, for reading and commenting on manuscript drafts.
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