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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Spinal pain and its consequences have developed into a modern epidemic. Unfortunately, effects of efforts to prevent 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), cervical 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

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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 Committees. 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 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

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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.

Table 1. Prevalence of included phenotypes in 15,328 Danish twins ages 20–71 years*
PhenotypeAge 20–35 yearsAge 36–50 yearsAge 51–71 years
MZDZPMZDZPMZDZP
  • *

    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.

Men, no.1,4531,587 1,2982,037 1,2202,461 
Women, no.2,0921,914 1,5502,299 1,3802,562 
Total, no.3,5453,501 2,8484,336 2,6005,023 
LBP in the past 12 months         
 Men         
  Any pain36.039.00.10849.345.60.04838.836.80.258
  1–30 days29.130.90.28538.235.70.16228.624.60.014
  >30 days7.58.50.31111.610.50.36310.511.60.379
  Sciatica10.213.30.01124.023.60.76621.322.20.547
 Women         
  Any pain41.744.00.17550.351.20.63741.440.80.770
  1–30 days30.932.10.46235.935.20.67023.622.50.468
  >30 days11.112.50.19115.317.10.16616.116.30.888
  Sciatica15.316.00.59427.226.90.81627.526.50.565
MBP in the past 12 months         
 Men         
  Any pain14.915.30.78512.110.50.1596.67.00.683
  1–30 days12.412.30.9399.89.10.4774.64.10.528
  >30 days2.73.50.2463.72.20.0242.32.70.492
  Sciatica4.44.60.8064.53.40.1133.74.70.172
 Women         
  Any pain15.815.70.99417.817.90.92610.412.10.126
  1–30 days11.611.40.86613.613.10.6535.36.10.388
  >30 days4.64.80.7375.66.50.2966.26.00.839
  Sciatica4.44.50.8167.36.80.5295.77.10.129
NP in the past 12 months         
 Men         
  Any pain23.125.60.12631.327.90.03921.022.40.350
  1–30 days18.620.60.19424.322.40.24614.914.90.959
  >30 days4.85.90.2299.17.40.1128.18.40.825
  Sciatica6.97.40.61412.811.90.45111.912.20.837
 Women         
  Any pain35.237.10.24247.146.40.71333.934.00.955
  1–30 days24.525.60.43432.330.90.38717.417.70.875
  >30 days11.412.40.36216.317.70.31616.015.60.788
  Sciatica12.613.50.41425.225.00.90323.422.40.545
Pain in >1 area         
 Men         
  LBP + MBP2.72.70.9661.81.80.9921.11.00.625
  LBP + NP7.48.70.18911.810.60.2777.57.40.945
  MBP + NP1.71.40.6500.80.80.8400.60.20.123
  LBP + MBP + NP6.36.90.5207.75.40.0082.93.50.286
 Women         
  LBP + MBP1.81.90.7871.31.90.1640.70.70.854
  LBP + NP11.013.10.04715.315.10.8718.47.70.441
  MBP + NP1.41.20.5181.21.30.8290.60.80.480
  LBP + MBP + NP9.99.60.69913.011.80.3165.96.80.256
Consequences of LBP         
 Men         
  Reduced physical activity12.112.00.90521.218.90.12017.217.50.839
  Sought care12.213.60.26318.517.60.50314.415.00.669
  Change work duty5.15.80.4548.78.10.5376.27.60.122
  Sick leave8.611.10.06612.412.40.9557.78.60.436
  Early pension0.40.70.3071.51.30.7462.43.90.027
 Women         
  Reduced physical activity11.412.60.28318.719.60.51418.319.10.536
  Sought care13.114.50.20220.620.60.99919.820.00.881
  Change work duty6.36.20.8209.010.70.1018.38.00.683
  Sick leave6.88.40.1439.411.10.13511.410.00.325
  Early pension0.60.90.2181.92.80.0864.95.10.779
Consequences of MBP         
 Men         
  Reduced physical activity3.95.00.1824.12.70.0252.23.00.187
  Sought care4.64.90.6994.34.40.8712.93.10.665
  Change work duty1.71.90.6201.71.30.4020.51.20.042
  Sick leave3.93.20.4022.21.70.3441.31.30.894
  Early pension0.10.30.3220.20.20.9310.81.00.591
 Women         
  Reduced physical activity3.23.90.2184.54.40.9344.55.20.411
  Sought care5.56.10.4377.97.30.5075.66.00.670
  Change work duty1.92.30.3942.92.70.7992.02.20.644
  Sick leave1.62.50.1252.22.20.9542.73.20.497
  Early pension0.20.50.2220.61.00.2981.41.70.529
Consequences of NP         
 Men         
  Reduced physical activity5.55.30.8588.46.70.0675.37.60.009
  Sought care8.08.10.88810.59.80.5387.69.30.089
  Change work duty1.62.30.1873.52.60.1631.92.50.287
  Sick leave4.24.50.7923.83.80.9533.32.60.348
  Early pension0.10.30.4850.70.50.5821.11.70.158
 Women         
  Reduced physical activity6.98.70.03614.312.80.18712.811.70.307
  Sought care12.714.20.20620.721.50.59716.217.30.402
  Change work duty3.33.50.7216.66.10.5715.25.40.801
  Sick leave5.07.00.0558.37.10.2435.06.40.211
  Early pension0.40.70.2101.31.80.2693.83.50.595

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.

thumbnail image

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.

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thumbnail image

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.

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thumbnail image

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.

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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 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.

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*
PhenotypeGenetic correlation (95% CI)Environmental correlation (95% CI)Phenotypic correlation (95% CI)Bivariate heritability (95% CI)
  • *

    95% CI = 95% confidence interval; LBP = low back pain; MBP = mid-back pain; NP = neck pain.

LBP + MBP    
 Men, years of age    
  20–350.54 (0.25–0.85)0.41 (0.26–0.55)0.45 (0.39–0.51)0.39 (0.16–0.62)
  36–501.00 (0.41–1.00)0.37 (0.24–0.50)0.46 (0.40–0.52)0.36 (0.11–0.59)
  51–711.00 (0.30–1.00)0.49 (0.34–0.64)0.54 (0.48–0.60)0.30 (0.05–0.55)
 Women, years of age    
  20–350.74 (0.57–0.93)0.50 (0.38–0.61)0.59 (0.55–0.63)0.47 (0.34–0.60)
  36–500.79 (0.55–1.00)0.52 (0.39–0.64)0.61 (0.56–0.65)0.43 (0.28–0.58)
  51–710.66 (0.45–0.89)0.54 (0.39–0.68)0.59 (0.54–0.64)0.45 (0.28–0.62)
LBP + NP    
 Men, years of age    
  20–350.62 (0.40–0.84)0.47 (0.34–0.59)0.52 (0.47–0.57)0.42 (0.24–0.59)
  36–500.86 (0.51–1.00)0.35 (0.23–0.47)0.47 (0.42–0.51)0.44 (0.24–0.63)
  51–710.54 (0.14–0.99)0.60 (0.48–0.70)0.57 (0.53–0.61)0.24 (0.04–0.42)
 Women, years of age    
  20–350.75 (0.61–0.89)0.46 (0.36–0.55)0.57 (0.53–0.61)0.51 (0.39–0.63)
  36–500.64 (0.47–0.80)0.49 (0.39–0.59)0.55 (0.51–0.58)0.45 (0.37–0.56)
  51–710.74 (0.58–0.90)0.53 (0.42–0.63)0.61 (0.57–0.65)0.47 (0.34–0.60)
MBP + NP    
 Men, years of age    
  20–350.69 (0.43–0.98)0.52 (0.37–0.65)0.58 (0.52–0.63)0.41 (0.21–0.59)
  36–500.76 (0.00–1.00)0.54 (0.42–0.67)0.54 (0.49–0.60)0.11 (0.00–0.34)
  51–711.00 (0.34–1.00)0.53 (0.41–0.65)0.60 (0.54–0.66)0.26 (0.02–0.50)
 Women, years of age    
  20–350.73 (0.56–0.91)0.54 (0.42–0.64)0.61 (0.57–0.65)0.46 (0.33–0.59)
  36–500.72 (0.49–1.00)0.57 (0.44–0.69)0.62 (0.57–0.66)0.39 (0.24–0.54)
  51–710.84 (0.65–1.00)0.58 (0.43–0.71)0.68 (0.64–0.73)0.50 (0.35–0.64)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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 Swedish 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 complex 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, 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

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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, Leboeuf-Yde.

Analysis and interpretation of data. Hartvigsen, Nielsen, Kyvik, Fejer, Vach, Iachine, Leboeuf-Yde.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We gratefully acknowledge Professor Tom Bendix, DrMedSci, for reading and commenting on manuscript drafts.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
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