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Research Paper

Heritability of musculoskeletal pain and pain sensitivity phenotypes: 2 generations of the Raine Study

Waller, Roba,*; Melton, Philllip E.b,c; Kendell, Michellea; Hellings, Sophiea; Hole, Erlenda; Slevin, Alisona; Soares, Jiana; Jacques, Angelaa; Straker, Leona; Beales, Darrena

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doi: 10.1097/j.pain.0000000000002411
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1. Introduction

Persistent musculoskeletal (MSK) pain is a leading cause of disability internationally and a major global burden in terms of health system costs, decreased quality of life, and lost productivity.6,21 The emergence of MSK pain is multidimensional in nature18,58 with genetic and environmental influences. Pain sensitivity may be an important dimension to understand because it has been associated with the risk of developing pain,22 persistence of pain,19,48 and a heightened pain experience.54,55,61 Another dimension of MSK pain is structural change. With genetics explaining as much as 75% of cervical and lumbar disk degeneration,47 it has been suggested structural changes could account for heritability of regional pain conditions such as low back pain. However, a large number of studies report a poor correlation between structural changes and pain severity for peripheral3,17,20,37 and spinal7,24,63 MSK pain disorders. Therefore, structural change may not be as relevant to the emergence of pain as pain genetics and nociceptive processing.39 Investigation of the genetic and environmental influence on hypersensitive nociceptive pathways, reflected in heightened pain sensitivity, may enhance understanding in the emergence of MSK pain.14,22 Assessment of heritability of pain and pain sensitivity may be beneficial in enhancing this understanding.

Heritability assessment allows for the investigation of complex, multifactorial disorders such as MSK pain and pain sensitivity. In twin studies, heritability estimates (which range from 0 to 1) for persistent low back pain vary from 0.21 to 0.6716 and from 0.27 to 0.71 for chronic widespread pain.29 Twin studies have investigated the heritability of pain sensitivity with one study estimating genetically mediated variance in cold-pressor pain at 0.60 and heat pain variance at 0.26.41 Another study reported heritability of pressure pain threshold (PPT) was nonsignificant at 0.10.31 Intergenerational studies represent an alternative approach to investigate heritability. For example, a large intergenerational study in 2195 extended families investigated chronic pain with impact estimates of heritability attributable to additive genetic effects after adjustment for confounders as 0.16 (SE 0.07; P = 0.02) for “any chronic pain” and 0.30 (SE 0.13; P = 0.007) for “severe” chronic pain.27 Currently, there is only one small study using 4 families suggesting partial intergenerational heritability of cold pain tolerance.5 One potential advantage of intergeneration studies over twin studies is that they may facilitate greater generalisation to the wider population.34,64

There is need for a greater understanding of biological factors that increase the risk for persistent pain and heightened pain sensitivity. Hence, the aim of this study was to investigate the heritability of MSK pain experience and pain sensitivity across two generations from the Raine Study while adjusting for potential confounders. Previous work in Raine Study Gen2 participants demonstrates family–social influences,43,60 genetic influences,49 and complex environmental influences on pain and pain sensitivity.50,61 Currently, there is a gap in our understanding of the heritability of pain and pain sensitivity and an improved understanding of what influences the development of pain and pain sensitivity can advance our understanding of pain disorders.

2. Methods

2.1. Study population

This was an intergenerational, cross-sectional study using data obtained from the Raine Study (www.rainestudy.org.au). The Raine Study is one of the most richly characterised prospective cohort studies in the world.15,53 There were 2900 pregnant women (Gen1) enrolled in the study with initial measures collected at 16- to 20-week gestation. There were 2868 children (Gen2) born between May 1989 and November 1991 entering the initial birth cohort. The current study used data obtained from the Gen1-26 year follow-up and the Gen2-22 year follow-up. The enrolled biological mothers and their partners make up Gen1, referred to as the maternal and paternal group in this study. A comparison between cohort participants at birth, childhood (year 8), adolescence (years 14 and 17), and young adulthood (years 20 and 22) on a range of characteristics including family structure, education, employment, income, and ethnicity has been reported previously showing the sample is widely representative of the Western Australian population.52 Ethics approval for the Gen1-26 year follow-up was obtained from the University of Western Australia (RA/4/1/7236). Ethics approval for the Raine Study Gen2-22 year follow-up was obtained from Curtin University (HR 23/2013) and the University of Western Australia (RA/4/1/5202). Specific approval for this project was obtained from the Curtin University Human Research Ethics Committee (HRE2018-0432) and the Raine Study (Project Number MUS0317).

2.2. Data collection at Gen1-26 year and Gen2-22 year follow-ups

Data for the Gen1 and Gen2 group were collected as part of 4 hours of testing followed by an overnight sleep study.53

The aim of the Gen2-22 year follow-up was to identify the incidence of critical health issues and behaviours in early adulthood. Participants completed questionnaires before undergoing physical assessments. Anthropometry and pain sensitivity measures were part of the physical assessment protocol conducted by Raine Study research staff, all of whom were thoroughly trained in the data collection procedures and used standardized protocols. The Gen2-22 year follow-up ran between March 2012 and July 2014 with 1234 of 2086 participants still “active” taking part in some aspect of the follow-up.

Data for the Gen1-26 year follow-up were collected using the same measures and protocols as was used at the Gen2-22 year follow-up, designed to enable intergenerational comparisons.15 The Gen1-26 year follow-up (referring to the data collected on Gen1 when the index [Gen2] participants were 26 years old) ran between April 2015 and June 2017. Parents were contacted if their children (Gen2) participated in the Gen2-22 year follow-up. Of 1772 active (eligible) parents, 1098 (636 mothers and 462 fathers) participated in the Gen1-26 year follow-up.

Participants were eligible for analysis in this study if they had matched parent–offspring pain and pain sensitivity data for at least one parent. In the case of Gen2 participants with siblings, the eldest sibling was included and other siblings removed (n = 30, including 19 twins and 2 triplets) because the focus of this intergenerational study was on triads (mother, father, and oldest offspring). A total of 631 mothers, 461 fathers, 688 offspring (343 daughters and 345 sons), and 405 triads were included for analysis.

2.3. Pain experience

Pain experience was characterised using a Pain Severity Index (PSI) determined using items based on the örebro MSK Pain Questionnaire (öMPQ). Participants who answered no to the question “Do you currently have any body pain?” were redirected away from answering further questions, and their PSI was scored as zero. For those participants who answered yes, their PSI score was determined using pain chronicity, number of pain areas, and pain intensity. Pain chronicity was scored using the öMPQ question “How long have you had your current pain problem?” (0 days = 1, 1-2 days = 2, 3-7 days = 3, 8-14 days = 4, 15-30 days = 5, 1 month = 6, 2 months = 7, 3-6 months = 8, 6-12 months = 9, and over 1year = 10). A count of pain areas (maximum 10) was calculated from the number of endorsed response options to a list of predefined body sites from the öMPQ question “Where do you have pain?“. Pain intensity was scored from the öMPQ question “How would you rate the pain that you have had during the past week?” using a numerical rating scale with 0 indicating “no pain” and 10 indicating “pain as bad as it could be.” The scores from these questions were added together to create a composite score ranging from 1 to 30.

2.4. Pain sensitivity measure

Pain sensitivity for parents and their offspring was measured using PPT and cold pain threshold (CPT) quantitative sensory testing. All testing was performed at a constant room temperature and unilaterally on the right side of the body because it has been shown there is side-to-side consistency in pain sensitivity measurement.46 A “method of limits” standardised protocol consistent with best practice recommendations was used.4 Testing of PPT was performed before CPT because cold stimuli can influence subsequent PPT by increasing the potential for mechanical hyperalgesia.23 Intrarater and interrater reliability with acceptable levels of standard error of measurement for PPT and CPT testing have both been demonstrated.36,62

2.5. Pressure pain thresholds

Pressure pain threshold was established using a pressure algometer (Somedic AB, Norra Mellby, Sweden) with a contact area of 1 cm2 that was applied perpendicular to the skin. The pressure was increased at a ramp rate of 50 kPa/s, and for safety purposes, the maximum pressure was limited to 1000 kPa. Standardized instructions read to the participants were as follows: “The moment the pressure increases to a point where it first feels uncomfortable or painful, press and release the button. This means the very first onset of discomfort or pain and not the most pressure that you can bear.” The lumbar spine (back), upper trapezius (neck), tibialis anterior (leg), and dorsal wrist (wrist) were all used as test sites, as per the testing protocol reported previously.62 Pressure pain threshold tests were performed 4 times at each site with a 10-second rest between each trial. A mean threshold was calculated from the last 3 trials at each site.59 When participants had valid PPT data from all test sites, a combined PPT score was computed from the mean PPT of all 4 test sites.52 Excellent interrater and intrarater reliability for PPT testing by Raine Study research staff has been demonstrated.62

2.6. Cold pain thresholds

Cold pain threshold was measured using an Advanced Thermosensory Stimulator 2, 2001 (Medoc) or an Modular Sensory Analyzer (Somedic) thermal stimulator with a thermode of 9.0 and 12.5 cm2, respectively, applied on the dorsum of the right wrist. Standardized instructions read to the participants were as follows: “Allow the temperature to drop until the moment it reaches a point where it feels uncomfortably or painfully cold, and then press the button. This means the very first onset of discomfort or pain and not the coldest that you can bear.” The temperature was set at a baseline of 32°C and decreased at a rate of 1°C/s to a cut off temperature of 5°C. Cold pain threshold tests were performed 4 times at each site with a 10-second rest between each trial. A mean threshold was calculated from the last 3 trials at each site.59

2.7. Other variables

To enable control for possible confounding of familial associations, several other variables were included. Inclusion of possible confounders was based on findings of previous investigations using Raine Study Gen2-22 year pain sensitivity data.59,61 Sex and age were provided. Waist and hip circumference were measured using a standardized protocol to calculate the waist to hip ratio. Participants were categorised as smokers or nonsmokers based on their current smoking status. Depression, anxiety, and stress-related symptoms were assessed using the validated and reliable Depression Anxiety Stress Scale-21 (DASS-21), with a higher score indicating greater severity of symptoms.26 The Pittsburgh Sleep Quality Index was used as a validated and reliable measure with perceived sleep quality and disturbance over a 1-month period, scored on a 0 to 21 scale with a score >5 indicative of poor sleep quality.9 Physical activity was assessed using the validated and reliable International Physical Activity Questionnaire, where participants were asked to record their weekly physical activity in hours based on their vigorous activity, moderate activity, how much they walked, and how much time they spent sitting.12 This was then categorised into low, moderate, and high physical activity levels.

2.8. Statistical analysis

Descriptive summaries of participant characteristics (sex, age, waist to hip ratio, smoking status, depression, anxiety, stress, sleep quality, and physical activity level), PSI, and pain sensitivity measures (PPT and CPT) were based on frequency distributions for categorical data and mean and SD or median and interquartile range for continuous data, depending on normality.

Familial aggregation was checked for PSI and pain sensitivity measures (PPT and CPT) using the correlation coefficient (r2) in different classes of familial relationships. Heritability estimates for all investigated traits were derived using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) software.1 The SOLAR program uses a variance component method to partition the observed covariance between the participants into genetic and environmental components. Each individual genetic and environmental variance component is accompanied by a structuring matrix that predicts the covariance among individuals associated to that component, allowing for the additional accounting of significant covariates in the model. Heritability (h2) is defined as the variance in the trait due to additive genetic effects and the stochastic (random/unmeasured) environmental effects.34 The null hypothesis of no heritability (h2 = 0) was tested by comparing the log likelihood of the full model (using familial relationships) with the reduced model (without familial relationships), using log-likelihood ratio tests. Twice the difference in log-likelihoods was distributed as a χ2 distribution with 1 degree of freedom. Owing to the potential of variance component–based heritability estimates to be influenced by elevated kurtosis, all variables were inverse normalized in SOLAR. We examined the additive genetic correlation (rG) by measuring the extent of common genetic effects on all pairs of pain sensitivity measures (PPT and CPT).2 If rG =  0, this means that two traits being analyzed are influenced by independent genetic factors. If rG = 1, then the genetic factors are completely shared. Sex, age, age2, smoking, sex by age, and sex by age2 interactions were included as covariates in the analyses. Age2 was included to account for potential nonlinear effects of age on each outcome. A significance threshold of 0.05 was used to determine statistical significance. To account for multiple testing, we used a Bonferroni method to establish the significance level.

3. Results

There were 1092 Gen1 participants included with a mean age (SD) of 56.7 (5.7) years, 631 (58%) were female and 461 (42%) were male. There were 688 Gen2 participants included with a mean age (SD) of 22.1 (0.6) years, 343 (50%) were female and 345 (50%) were male. Characteristics of the participants are presented in Table 1, stratified by generation and sex. Correlation coefficients between interfamilial relationships and spouses and between unrelated sons and daughters are presented in Table 2. The highest correlation coefficient was seen for neck pain between fathers and daughters (0.20) and the lowest was for CPT (−0.05) in the unrelated group for sons and daughters. After accounting for multiple testing using a conservative Bonferroni approach (0.05/7 = 0.007), a total of 9 pain sensitivity pairs remained significant, with 9 between intraclass relative PPT pairs and one in the unrelated spouses (neck PPT). No CPT pain sensitivity pairs were significant.

Table 1 - Participant characteristics.
Variable Mothers n = 631 Fathers n = 461 Daughters n = 343 Sons n = 345
Age (yr), mean (SD) 55.6 (5.5) 58.2 (5.7) 22.1 (0.6) 22.1 (0.6)
Waist-hip ratio*, mean (SD) 0.88 (0.07) 0.97 (0.07) 0.80 (0.07) 0.86 (0.06)
Smoking, n (%) yes 67 (11.2) 41 (9.6) 43 (13.2) 51 (16.1)
Depression (DASS-21); range 0-42, median (IQR) 2 (0-6) 2 (0-6) 4 (2-12) 2 (0-8)
Anxiety§ (DASS-21); range 0-42, median (IQR) 2 (0-4) 2 (0-4) 4 (0-8) 2 (0-6)
Stressǁ (DASS-21); range 0-42, median (IQR) 4 (2-10) 4 (0-10) 10 (4-16) 6 (2-10)
Sleep quality (PSQI total); range 0-21, mean (SD) 6.0 (3.3) 5.2 (3.0) 4.9 (2.3) 4.2 (2.2)
Activity level# (IPAQ), n (%)
 Low 189 (30.9) 102 (23.2) 67 (20.4) 38 (12.0)
 Moderate 212 (34.6) 143 (32.5) 88 (26.8) 56 (17.7)
 High 211 (34.5) 195 (44.3) 173 (52.7) 223 (70.4)
 Pain Severity Index (for those with pain), range 1-30, mean (SD)** 15.1 (5.0) 14.1 (4.9) 14.5 (4.7) 13.0 (3.5)
Pressure pain threshold (kPa), median (IQR)
 Back†† 406 (294-538) 569 (416-751) 346 (236-461) 520 (351-743)
 Neck‡‡ 299 (217-408) 416 (288-618) 217 (156-322) 297 (212-444)
 Leg§§ 381 (274-484) 520 (383-680) 346 (250-485) 474 (347-716)
 Wristǁǁ 330 (260-426) 449 (344-581) 332 (259-446) 452 (346-662)
 Combined all 4 sites¶¶ 1454 (1093-1820) 1985 (1509-2608) 1289 (931-1707) 1718 (1302-2510)
 Cold pain threshold## (°C), median (IQR) 5 (5-12) 5 (5-8) 13 (6-23) 7 (5-16)
Missing data:
*Waist to hip ratio = 39, 2, 19, and 0 missing, respectively, from mothers, daughters, fathers, and sons.
Smoking = 33, 17, 32, and 29 missing, respectively, from mothers, daughters, fathers, and sons.
Depression = 39, 24, 36, and 48 missing, respectively, from mothers, daughters, fathers, and sons.
§Anxiety= 37, 24, 32, and 48 missing, respectively, from mothers, daughters, fathers, and sons.
ǁStress = 43, 26, 39, and 50 missing, respectively, from mothers, daughters, fathers, and sons.
Sleep quality = 59, 40, 28, and 64 missing, respectively, from mothers, daughters, fathers, and sons.
#Activity levels = 19, 15, 21, and 28 missing, respectively, from mothers, daughters, fathers, and sons.
**Pain Severity Index (for those with pain) n = 487 (78%), 135 (39%), 332 (72%), and 93 (27%) for mothers, daughters, fathers, and sons, respectively.
††Pressure pain threshold (back) = 68, 9, 38, and 5 missing, respectively, from mothers, daughters, fathers, and sons.
‡‡Pressure pain threshold (neck) = 64, 7, 34, and 5 missing, respectively, from mothers, daughters, fathers, and sons.
§§Pressure pain threshold (leg) = 59, 8, 35, and 5 missing, respectively, from mothers, daughters, fathers, and sons.
ǁǁPressure pain threshold (wrist) = 58, 7, 31, and 2 missing, respectively, from mothers, daughters, fathers, and sons.
¶¶Pressure pain threshold (all) = 72, 12, 41, and 10 missing, respectively, from mothers, daughters, fathers, and sons.
##Cold pain threshold = 64, 14, 47, and 14 missing, respectively, from mothers, daughters, fathers, and sons.
DASS-21, Depression Anxiety Stress Scale-21; IPAQ, International Physical Activity Questionnaire; IQR, interquartile range; PSQI, Pittsburgh Sleep Quality Index.

Table 2 - Interfamilial correlations plus standard deviations and (P values) for pain sensitivity traits in intergenerational Raine Study families.
Pressure pain threshold
First degree class Pain Severity Index Back Neck Leg Wrist Combined Cold pain threshold
Interclass
 Father–child 0.119±0.054* (<0.01) 0.08±0.05 (<0.09) 0.129±0.05 (<0.008) 0.126±0.05 (<0.01) 0.141±0.05* (<0.003) 0.140±0.05* (<0.005) 0.04±0.05 (<0.41)
 Mother–child 0.104±0.04 (<0.01) 0.103±0.04 (<0.01) 0.148±0.04* (<0.0004) 0.102±0.04 (<0.02) 0.081±0.04 (<0.06) 0.119±0.04* (<0.005) 0.05±0.04 (<0.22)
 Father–daughter (222 pairs) 0.183±0.07* (<0.007) 0.077±0.07 (<0.28) 0.183±0.07 (<0.008) 0.113±0.07 (<0.11) 0.142±0.07 (<0.04) 0.161±0.07 (<0.02) −0.012±0.07 (<0.87)
 Mother–daughter (317 pairs) 0.132±0.06 (<0.02) 0.159±0.06 (<0.008) 0.131±0.06 (<0.02) 0.101±0.06 (<0.09) 0.038±0.06 (<0.52) 0.125±0.06 (<0.03) 0.027±0.06 (<0.66)
 Father–son (233 pairs) 0.04±0.07 (<0.52) 0.124±0.07 (<0.07) 0.133±0.07 (<0.05) 0.169±0.07 (<0.01) 0.173±0.07 (<0.01) 0.168±0.07 (<0.02) 0.11±0.07 (<0.12)
 Mother–son (310 pairs) 0.047±0.06 (<0.42) 0.167±0.06* (<0.005) 0.204±0.06* (<0.0006) 0.134±0.06 (<0.02) 0.103±0.06 (<0.09) 0.169±0.06* (<0.005) 0.083±0.06 (<=0.17)
Unrelated
 Father–mother (405 pairs) 0.03±0.05 (<0.53) 0.062±0.05 (<0.24) 0.162 ±0.05* (<0.002) 0.067±0.05 (<0.20) 0.132±0.05 (<0.01) 0.126±0.05 (<0.01) 0.099±0.05 (<0.06)
 Sons–daughters −0.01±0.04 (<0.73) 0.09±0.04 (<0.04) 0.02±0.04 (<0.58) 0.058±0.04 (<0.18) 0.01±0.04 (<0.76) 0.058±0.04 (<0.19) −0.05±0.04 (<0.245)
*Significant difference with a P value<0.007.

Heritability (h2) estimates for pain (PSI) and pain sensitivity (PPT and CPT separately) are reported in Table 3 (n = 405 triads). Waist to hip ratio, depression, anxiety, stress, sleep quality, and activity level were not significant and were dropped from the final model. Age, sex, and smoking status were retained because they were significant in all regression models used to calculate heritability. After adjustment, PSI heritability was estimated to be 0.254 (SE = 0.063, P = 4.7e-05). Pressure pain threshold heritability was significant at the back (h2 = 0.215, SE = 0.064, P = 0.0005), neck (h2 = 0.289, SE = 0.059, P = 2.e−05), leg (h2 = 0.190, SE = 0.064, P = 0.002), and wrist (h2 = 0.179, SE = 0.064, P = 0.002). Consistent with this, heritability for the PPT of all sites combined was also significant (h2 = 0.212, SE = 0.064, P = 0.0004). Cold pain threshold heritability was not significant and estimated to be 0.073 (SE = 0.061, P = 0.11).

Table 3 - Pain severity and pain sensitivity heritability estimates (n = 405 triads).
Trait h2 SE P n Significant covariates 95% CI Sporadic model log likelihood Polygenic model log likelihood Proportion of variance
Pain severity index 0.254* 0.063 4.74e-05 1741 Age, age2, and smoking 0.131-0.378 −583.05 −575.43 0.172
Pressure pain threshold
 Back 0.215* 0.064 0.0005 1566 Age, sex, age2, Age2*Sex, and smoking 0.081-0.325 −645.005 −639.63 0.146
 Neck 0.289* 0.059 2.e−05 1675 Age and sex 0.125-0.357 −704.74 −696.39 0.140
 Leg 0.190* 0.064 0.002 1576 Age, sex, Age2*Sex, and smoking 0.065-0.315 −672.13 −667.79 0.124
 Wrist 0.179* 0.064 0.002 1585 Sex, age2, smoking, 0.084-0.330 −674.17 −670.36 0.125
 Combined 0.212* 0.064 0.0004 1551 Age, sex, Age2*Sex, and smoking 0.108-0.358 −633.55 −627.91 0.149
Cold pain threshold 0.073 0.061 0.11 1646 Age, sex, and Age*Sex −0.047-0.193 −4034.40 −4033.68 0.097
Models adjusted for age, sex, and smoking status.
*Heritability is significantly different with a P value<0.007.
CI, confidence interval; h2, heritability.

Genetic and phenotypic correlations between all pairs of pain sensitivity measures (PPT and CPT) are presented in Table 4. The highest positive genetic correlations are shown with the combined PPT and all other PPT traits (0.89-0.957) and indicate that there are likely shared genetic factors between these traits. The lowest negative genetic correlations were shown between PPT and CPT measures indicating little or no genetic components shared between traits. The observed phenotypic correlations demonstrate a similar pattern as the genetic correlation with the combined PPT and other PPT traits demonstrating high positive correlations and PPT traits vs CPT showing negative correlations.

Table 4 - Genetic and phenotypic correlations between all pairs of pain sensitivity measures (pressure pain threshold and cold pain threshold).
Pressure pain threshold
Back Neck Leg Wrist Combined Cold pain threshold
Pressure pain threshold
 Back 1 0.739 0.791 0.699 0.912 −0.399
 Neck 0.901* (0.09) 1 0.739 0.686 0.872 −0.347
 Leg 0.844* (0.08) 0.839*, (0.10) 1 0.751 0.920 −0.351
 Wrist 0.778*, (0.11) 0.900* (0.11) 0.797* (0.10) 1 0.866 −0.333
 Combined 0.957* (0.03) 0.956* (0.04) 0.931* (0.03) 0.891* (0.06) 1 −0.404
Cold pain threshold −0.849* (0.25) −0.812* (0.25) −0.892* (0.27) −0.574 (0.26) −0.842* (0.23) 1
Genetic correlations with standard error are shown in lower half of table and phenotypic correlations are displayed in upper half.
*Genetic correlation is significantly different from 0 with a P value <0.05.
Genetic correlation is significantly different from 1 with a P value <0.05.

4. Discussion

This study is the largest intergenerational investigation of the heritability of both MSK pain and pain sensitivity. The findings suggest an underlying genetic component to the pain experience and pressure pain sensitivity that accounts for between 0.190 and 0.289 of the variation in the phenotype. The lower interfamilial correlations reported compared with the observed heritability estimates support that there is an underlying genetic component contributing to the pain experience and pressure pain sensitivity. This aligns to previous reported heritability estimates for pain experience and provides new insights into heritability of pressure pain sensitivity. By contrast, the heritability estimate for cold pain sensitivity was not significant, suggesting different underlying mechanisms from pressure pain sensitivity.

4.1. Strengths, limitations, and methodological considerations

A major strength of this study is the large sample size with a broad range of data allowing for consideration of several confounders including smoking status, psychological status, and physical activity. The Raine Study is a population-based cohort, representative of the general population,52 meaning there was no ascertainment bias. A non-twin study design has not been previously performed to investigate the heritability of pain sensitivity. The use of SOLAR ensured robust statistical analysis that has been mathematically derived and previously validated on a data set with known heritability parameters.33 The use of the PSI provided a broad estimate of the pain experience rather than relying on a single unidimensional measure61 and addresses previous recommendations for investigating heritability of pain.39 Pain sensitivity data were collected according to best practice recommendations.4

Potential limitations and methodological consideration include that participants were primarily of Caucasian ancestry living in a Mediterranean-style climate, and therefore, these findings may not be generalizable to other ethnic populations living in different geographical locations.45 Although the PSI is related to only MSK pain and we did not capture specific MSK diagnoses (though most pain disorders are nonspecific in nature30), the heritability estimates observed in the study are comparable with earlier studies of pain-related traits in other ethnicities. Although we had pressure sensitivity data at multiple sites, considerations related to participant burden meant we only had a single site for cold pain sensitivity. Pressure pain threshold and CPT are static measures of pain sensitivity that might not provide insights into the efficiency of central nociceptive processing that dynamic sensory testing can provide (eg, temporal summation and conditioned pain modulation).35 In addition, pain sensitivity measurements were measured at only one time point, with the measures for Gen1 and Gen2 at separate times, and there was no control for contemporaneous medication or recreational drug use. Therefore, the pain sensitivity measures represent a snapshot in time and as such may be influenced by environmental factors that may also cluster in families that we were unable to consider. Further research might consider whether the balance of environmental vs genetic factors changes over time. Repeated pain sensitivity measurement at multiple time points may result in lowered within-person variability; however, the heritability estimates remain significant indicating robustness of the results. Although we have identified the possibility of underlying genetic mechanisms affecting pain experience and sensitivity, specific genes or genetic variants associated with these traits were not investigated.

4.2. Comparison with previous knowledge

Heritability of pain and pain sensitivity has previously been estimated using twin studies including monozygotic and dizygotic twins39,40; however, there are advantages of familial studies over twin studies. Twin studies may overestimate heritability because of the assumption that monozygotic twins are genetically identical, which is not always the case,8,56 and that there can be generalisation from twins to singletons.38 In addition, twin studies assume an “equal environment” for monozygotic and dizygotic twins, which is not always the case for monozygotic twins who can be epigenetically dissimilar.11 At age 22 years, young adults will have undergone significant changes in social environment, most likely sharing their social environment more with peers than parents or sibling twin.10 Evidence suggests estimating heritability using familial studies is an alternative approach that may facilitate generalization of results to the wider population.34,64

A significant estimate for the heritability of the MSK pain experience was identified in this study (h2 = 0.25). The best comparison study is by Hocking et al. that also used SOLAR and reported heritability of chronic MSK pain in extended families (n = 2195) after adjusting for confounders of age, sex, BMI, income, occupation, and physical activity. The results of heritability estimates of two phenotypes of chronic pain, “any chronic pain” and “severe chronic pain” (h2 = 0.16 and 0.30 respectively), show a near 2-fold increase in the heritability of “severe chronic pain” compared with “any chronic pain.” The use of the PSI in this study is equitable to the method of pain assessment in the Hocking et al. study, which both account for multiple aspects of the pain experience (eg, chronicity and intensity) to categorise severity of the pain experience in participants. Similarly, higher heritability of disabling low back pain vs inconsequential low back pain has been reported in a systematic review of 7 twin studies (n = 35,547).16 An analysis of 15,328 Danish twins (44% monozygotic and 56% dizygotic) reported comparable heritability of pain across the 3 spinal regions25 suggesting the heritability of MSK pain is similar across body sites. A systematic review of twin studies of pain also reported comparable heritability across many clinical pain conditions.39 A major limitation discussed in the Nielsen systematic review was the reliance on dichotomous pain outcomes39; a limitation this study addressed by the use of the PSI. Taken together, our estimate of the heritability for the experience of MSK pain are similar to those reported in the literature, supporting the consistency of the estimate across MSK sites, across pain conditions, and in varying ethnicities and geographical locations.

Heritability estimates for pressure pain sensitivity (0.25) and cold pain sensitivity (0.10) significantly adds to the current literature. One previous study was identified that estimated heritability of pressure pain sensitivity with PPT assessed on the forehead of 269 monozygotic (mean age 57.4 years) and 340 dizygotic (mean age 52.3 years) twin pairs with a nonsignificant 0.10 heritability estimate reported.31 The results potentially reflect on overestimation of the shared environment, particularly considering the high average age where the shared environment would have lessened considerably since adolescence. There are also notable methodological concerns with twins tested in the same room together and PPT only measured once. Similarly, only one other study was identified that estimated heritability of cold pain sensitivity using a cold-pressor pain test in 53 monozygotic and 29 dizygotic twins, aged 23 to 35 years.41 While heritability was estimated at 0.60, there were wide 95% confidence intervals reported (0.35-0.70) reflecting the small sample size, and there was no control for confounders such as age, sex, and smoking.

The finding of significant heritability for pressure but not cold pain sensitivity is of interest when considering how the environment may influence the development of pain sensitivity.14,60 Previous findings from the Raine Study Gen2 included that cold but not pressure pain sensitivity was associated with a heightened MSK pain experience.61 Cold sensation is processed through the sympathetic nervous system, which is intimately involved in central nociceptive processing,57 and can be sensitized by an altered stress regulation system, particularly the hypothalamic–pituitary–adrenal axis.44,51 Literature highlights environmental influences from pain events or social adversity at critical life phases, such as early life and adolescence, can result in enduring changes in the stress response system.14,32 A study of Raine Study Gen2 participants reported that for those with a higher MSK pain experience at 22 years, poor family functioning at 3 years increased the odds for high cold pain sensitivity (3.0, 95% confidence interval: 1.6-5.6).60 The lower heritability of cold pain sensitivity may reflect poorer stability over time39; however, the temporal relationship between cold pain sensitivity, environmental influences, and emergence of the MSK pain experience is currently unknown, particularly during adolescence10,60 when MSK pain becomes increasingly prevalent with persistent pain presentations and behaviours rapidly emerging.28,42

The findings suggest cold pain sensitivity may not be heritable, and given the association of cold pain sensitivity with a heightened pain experience, understanding environmental factors influencing the development of cold pain sensitivity may be one among many important factors to understand in the emergence of MSK pain. The global impact of pain highlights the need to understand the biology of pain and new targets for management. Understanding genetic and epigenetic factors that contribute to molecular mechanisms underlying persistent pain can provide targets for pain management.13 Although little is known on the role of pain sensitivity in the emergence of pain, if it is shown to be an important factor, the identification of important environmental influences of pain sensitivity could point to potential novel therapeutic interventions in the future that can prevent and treat pain. Practitioners could consider the contribution of environmental factors in clinical practice. This study highlights the need for further research investigating genetic, epigenetic, and environmental influences together to better understand mechanisms behind the emergence, remittance, or maintenance of chronic pain.

5. Conclusions

This unique investigation provides support for the heritability of MSK pain and pain sensitivity. The findings of significant heritability of pressure pain sensitivity and nonsignificant heritability of cold pain sensitivity are discussed and highlight how understanding environmental and genetic influences on the development of pain sensitivity are important. This together with an increased understanding of the role of pain sensitivity in the development or maintenance of pain may lead to opportunities to prevent future pain.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Acknowledgements

The authors would like to acknowledge the Raine Study participants and their families for their ongoing contribution to the study, the Raine Study staff for cohort coordination and data collection, and the UWA Centre for Sleep Science for utilisation of the facility and the sleep study technicians. The core management of the Raine Study is funded by the University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine Study Gen2-22 year follow-up was funded by NHMRC project grants 1027449, 1044840, and 1021855. Funding was also generously provided by Safe Work Australia. The Raine Study Gen1-26 year follow-up was funded by NHMRC project grants 1102106 and 1109057.

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Keywords:

Heritability; Musculoskeletal pain; Pain sensitivity; Raine Study

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