Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.
Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6–7%) than in other European populations (1–2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.
Disability retirement causes a significant burden on the society and affects the well-being of individuals. Early health problems as determinants of disability retirement have received little attention. The objective was to study, whether interrupting compulsory military service is an early indicator of disability retirement among Finnish men and whether seeking medical advice during military service increases the risk of all-cause disability retirement and disability retirement due to mental disorders and musculoskeletal diseases. We also looked at secular trends in these associations. We examined a nationally representative sample of 2069 men, who had entered military service during 1967–1996. We linked military service health records with cause-specific register data on disability retirement from 1968 to 2008. Secular trends were explored in three service time strata. We used the Cox regression model to estimate proportional hazard ratios and their 95% confidence intervals. During the follow-up time altogether 140 (6.8%) men retired due to disability, mental disorders being the most common cause. The men who interrupted service had a remarkably higher cumulative incidence of disability retirement (18.9%). The associations between seeking medical advice during military service and all-cause disability retirement were similar across the three service time cohorts (overall hazard ratio 1.40 per one standard deviation of the number of visits; 95% confidence interval 1.26–1.56). Visits due to mental problems predicted disability retirement due to mental disorders in the men who served between 1987 and 1996 and a tendency for a similar cause-specific association was seen for musculoskeletal diseases in the men who served in 1967–1976. In conclusion, health problems—in particular mental problems—during late adolescence are strong determinants of disability retirement. Call-up examinations and military service provide access to the entire age cohort of men, where persons at risk for work disability can be identified and early preventive measures initiated.
Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 × 10−10 for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate
closely with overall adiposity. Although rare mutations in the leptin (LEP)
gene are well known to cause leptin deficiency and severe obesity, no common loci
regulating circulating leptin levels have been uncovered. Therefore, we performed a
genome-wide association study (GWAS) of circulating leptin levels from 32,161
individuals and followed up loci reaching
P<10−6 in 19,979 additional individuals.
We identify five loci robustly associated (P<5 ×
10−8) with leptin levels in/near LEP,
SLC32A1, GCKR, CCNL1 and FTO. Although the
association of the FTO obesity locus with leptin levels is abolished by
adjustment for BMI, associations of the four other loci are independent of
adiposity. The GCKR locus was found associated with multiple metabolic traits
in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments
in mouse adipose tissue explants show convincing evidence for adipogenin, a
regulator of adipocyte differentiation, as the novel causal gene in the
SLC32A1 locus influencing leptin levels. Our findings provide novel
insights into the regulation of leptin production by adipose tissue and open new
avenues for examining the influence of variation in leptin levels on adiposity and
This meta-analysis of genome-wide association studies identifies four
genetic loci associated with circulating leptin levels independent of adiposity.
Examination in mouse adipose tissue explants provides functional support for the
To increase our understanding of the genetic basis of adiposity and its links to
cardiometabolic disease risk, we conducted a genome-wide association meta-analysis
of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci
reached genome-wide significance (P<5 ×
10−8), of which eight were previously associated with
increased overall adiposity (BMI, BF%) and four (in or near
COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel
associations with BF%. Seven loci showed a larger effect on
BF% than on BMI, suggestive of a primary association with adiposity,
while five loci showed larger effects on BMI than on BF%, suggesting
association with both fat and lean mass. In particular, the loci more strongly
associated with BF% showed distinct cross-phenotype association
signatures with a range of cardiometabolic traits revealing new insights in the link
between adiposity and disease risk.
A genome-wide association meta-analysis study here shows novel genetic
loci to be associated to body fat percentage, and describes cross-phenotype association
that further demonstrate a close relationship between adiposity and cardiovascular
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
Adult body size and body shape differ substantially between men and women and change over time. More than 100 genetic variants that influence body mass index (measure of body size) or waist-to-hip ratio (measure of body shape) have been identified. While there is evidence that some genetic loci affect body shape differently in men than in women, little is known about whether genetic effects differ in older compared to younger adults, and whether such changes differ between men and women. Therefore, we conducted a systematic genome-wide search, including 114 studies (>320,000 individuals), to specifically identify genetic loci with age- and or sex-dependent effects on body size and shape. We identified 15 loci of which the effect on BMI was different in older compared to younger adults, whereas we found no evidence for loci with different effects in men compared to women. The opposite was seen for body shape as we identified 44 loci of which the effect on waist-to-hip ratio differed between men and women, but no difference between younger and older adults were observed. Our observations may provide new insights into the biology that underlies weight change with age or the sexual dimorphism of body shape.
The prevalence of PI*Z and PI*S alleles of SERPINA1 gene related to alpha-1-antitrypsin deficiency has previously been estimated to be lower in Finland than in the other countries of Northern Europe. The prevalence of PI*M (Malton) has not been studied in Finland before. We determined alpha-1-antitrypsin PI*Z and PI*S and PI*M (Malton) genotypes from a representative population sample. The number of subjects was 6,354 in the PI*S and PI*M (Malton) genotyping. PI*Z genotyping was performed in a subsample of 2,482 subjects. The allele frequencies were PI*Z 19.7/1,000 and PI*S 10.2/1,000. No PI*M (Malton) was found. The number of carriers of PI*Z and PI*S is significantly higher than previously estimated. The prevalences are in line with the findings in the neighboring countries.
alpha-1-antitrypsin deficiency; Europe; Finland; genetic epidemiology; PI*Z; PI*S; PI*M (Malton); prevalence; SERPINA1
Many studies use information on weight histories to examine the association between body weight and mortality. A recent paper in EPIDEMIOLOGY (2013;24(1):158–166) developed a typology of the most common weight-history specifications.
We use data from a sample of Finnish adults to explore the associations of body weight and mortality, using existing specifications and also peak BMI, a new specification.
We confirm earlier findings that longer time in a high BMI state is predictive of mortality. Peak BMI (the highest BMI attained in life or available in the data) is also positively associated with mortality.
The specifications of duration in a high BMI state and peak BMI are both valuable for understanding the relationship between lifetime weight dynamics and mortality. The collection of information on peak body weight may be useful when collection of more detailed weight histories is not feasible.
To assess the association between being overweight or obese with low back pain (LBP) and clinically defined low back disorders across the life course.
A longitudinal and cross-sectional study.
A nationwide health survey supplemented with data from records of prior compulsory military service.
Premilitary health records (baseline) were searched for men aged 30–50 years (n=1385) who participated in a national health examination survey (follow-up).
Methods and outcome measures
Height and weight were measured at baseline and follow-up, and waist circumference at follow-up. Weight at the ages of 20, 30, 40 and 50 years were ascertained, when applicable. Repeated measures of weight were used to calculate age-standardised mean body mass index (BMI) across the life course. The symptom-based outcome measures at follow-up included prevalence of non-specific and radiating LBP during the previous 30 days. The clinically defined outcome measures included chronic low back syndrome and sciatica.
Baseline BMI (20 years) predicted radiating LBP in adulthood, with the prevalence ratio (PR) being 1.26 (95% CI 1.08 to 1.46) for one SD (3.0 kg/m2) increase in BMI. Life course BMI was associated with radiating LBP (PR=1.23; 95% CI 1.03 to 1.48 per 1 unit increment in Z score, corresponding to 2.9 kg/m2). The development of obesity during follow-up increased the risk of radiating LBP (PR=1.91, 95% CI 1.03 to 3.53). Both general and abdominal obesity (defined as waist-to-height ratio) were associated with radiating LBP (OR=1.64, 95% CI 1.02 to 2.65 and 1.44, 95% CI 1.02 to 2.04). No associations were seen for non-specific LBP.
Our findings imply that being overweight or obese in early adulthood as well as during the life course increases the risk of radiating but not non-specific LBP among men. Taking into account the current global obesity epidemic, emphasis should be placed on preventive measures starting at youth and, also, measures for preventing further weight gain during the life course should be implemented.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
To study the performance of a developed job exposure matrix (JEM) for the assessment of psychosocial factors at work in terms of accuracy, possible misclassification bias and predictive ability to detect known associations with depression and low back pain (LBP).
Materials and Methods
We utilized two large population surveys (the Health 2000 Study and the Finnish Work and Health Surveys), one to construct the JEM and another to test matrix performance. In the first study, information on job demands, job control, monotonous work and social support at work was collected via face-to-face interviews. Job strain was operationalized based on job demands and job control using quadrant approach. In the second study, the sensitivity and specificity were estimated applying a Bayesian approach. The magnitude of misclassification error was examined by calculating the biased odds ratios as a function of the sensitivity and specificity of the JEM and fixed true prevalence and odds ratios. Finally, we adjusted for misclassification error the observed associations between JEM measures and selected health outcomes.
The matrix showed a good accuracy for job control and job strain, while its performance for other exposures was relatively low. Without correction for exposure misclassification, the JEM was able to detect the association between job strain and depression in men and between monotonous work and LBP in both genders.
Our results suggest that JEM more accurately identifies occupations with low control and high strain than those with high demands or low social support. Overall, the present JEM is a useful source of job-level psychosocial exposures in epidemiological studies lacking individual-level exposure information. Furthermore, we showed the applicability of a Bayesian approach in the evaluation of the performance of the JEM in a situation where, in practice, no gold standard of exposure assessment exists.
Obesity, particularly visceral adiposity, is a major risk factor for type 2 diabetes. The commonly used obesity indicators, BMI, waist girth, and waist-to-hip ratio (WHR), have limited ability to measure the visceral adipose tissue. Sagittal abdominal diameter (SAD) has been shown to predict the amount of visceral fat. So far no study has been published on its ability to predict diabetes occurrence.
RESEARCH DESIGN AND METHODS
We assessed and compared the prediction of the four obesity indicators for diabetes incidence in a prospective study based on 5,168 participants from the nationally representative Health 2000 study.
During a mean follow-up lasting 8.1 years, 222 incident diabetes cases occurred. In multivariate models adjusted for lifestyle factors, BMI, waist girth, WHR, and SAD were significant predictors of diabetes incidence. The relative risks (95% CI) between high and low levels were 15.0 (6.94–32.6), 11.4 (5.39–23.8), 12.5 (6.47–24.2), and 14.7 (6.89–31.2), respectively. Pairwise interaction analysis showed that the co-occurrence of high BMI and high SAD was associated with the highest diabetes incidence, with a relative risk of 37.0 (11.2–122). After adjustment for waist girth and the components of the metabolic syndrome, the relative risk was 9.88 (2.81–34.7). The corresponding population-attributable fraction estimate was 84% (49–95).
The combination of SAD and BMI measurements yields a new predictor of diabetes incidence.
The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers.
Nicotinic acetylcholine receptors; 15q25.1; alcohol use; smoking behavior; public health; population-based sample; genetic association
The objective of this study was to assess the agreement and the repeatability of two methods measuring habitual coffee consumption, and to examine their homogeneity by socioeconomic and lifestyle factors.
Data on coffee consumption were collected for 4,254 subjects from a health questionnaire (HQ) and from a 1-year dietary history interview (DHI) used as the reference method during the Finnish Mobile Clinic Health Examination Survey conducted in 1973–1976. Short-term repeatability of the methods was assessed based on 286 and 93 subjects who repeated the HQ and the DHI after an interval of 4–8 months, respectively. The strength of agreement between the two methods and between the repeated measurements was estimated using the intraclass correlation coefficient (ICC).
The ICC was 0.86 for the agreement between the HQ and the DHI, and 0.77 and 0.85 for the repeatability of the HQ and the DHI, respectively. No statistically significant systematic differences in the mean intake values were found between the two methods or repeated measurements. The agreement and repeatability showed only minor differences in subgroups of background variables, with somewhat higher ICC values among subjects with a healthier lifestyle and higher education.
The study showed that the health questionnaire was a useful tool for measuring habitual coffee consumption for purposes of epidemiological research, due to its high reliability and homogeneity.
agreement; coffee; lifestyle; repeatability; socioeconomic factors
Vertebral fractures predict mortality, but little is known about their associations with the causes of death. We studied vertebral fractures for prediction of cause-specific mortality.
Material and methods
A nationally representative sample of 3,210 men and 3,730 women participated Mini-Finland health survey in 1978–1980. Vertebral fractures at the Th1–Th12 levels were identified from chest radiographs at baseline. Cox’s proportional hazard model was used to estimate the strength of association between vertebral fracture and mortality.
The relative risk (95% confidence interval) of death from natural causes was 1.49 (0.89–2.48) in men and 0.89 (0.60–1.31) in women with vertebral fractures (adjusted for age, body mass index, serum 25-hydroxyvitamin D, educational level, smoking, alcohol intake, physical activity and self-rated general health). Among women the adjusted relative risk of an injury death was 8.51 (3.48–20.77), whereas none of the men with vertebral fracture died due to an injury.
The patterns of mortality predicted by fracture in the thoracic spine differ between men and women.
Vertebral fracture; Osteoporosis; Hip fracture; Cause-specific mortality
The aim was to construct and validate a gender-specific job exposure matrix (JEM) for physical exposures to be used in epidemiological studies of low back pain (LBP).
Materials and Methods
We utilized two large Finnish population surveys, one to construct the JEM and another to test matrix validity. The exposure axis of the matrix included exposures relevant to LBP (heavy physical work, heavy lifting, awkward trunk posture and whole body vibration) and exposures that increase the biomechanical load on the low back (arm elevation) or those that in combination with other known risk factors could be related to LBP (kneeling or squatting). Job titles with similar work tasks and exposures were grouped. Exposure information was based on face-to-face interviews. Validity of the matrix was explored by comparing the JEM (group-based) binary measures with individual-based measures. The predictive validity of the matrix against LBP was evaluated by comparing the associations of the group-based (JEM) exposures with those of individual-based exposures.
The matrix includes 348 job titles, representing 81% of all Finnish job titles in the early 2000s. The specificity of the constructed matrix was good, especially in women. The validity measured with kappa-statistic ranged from good to poor, being fair for most exposures. In men, all group-based (JEM) exposures were statistically significantly associated with one-month prevalence of LBP. In women, four out of six group-based exposures showed an association with LBP.
The gender-specific JEM for physical exposures showed relatively high specificity without compromising sensitivity. The matrix can therefore be considered as a valid instrument for exposure assessment in large-scale epidemiological studies, when more precise but more labour-intensive methods are not feasible. Although the matrix was based on Finnish data we foresee that it could be applicable, with some modifications, in other countries with a similar level of technology.
The aim of this study was to explore long-term predictors of leisure time physical activity in the general population.
This study comprised 718 men and women who participated in the national Mini-Finland Health Survey from 1978–1980 and were re-examined in 2001. Participants were aged 30–80 at baseline. Measurements included interviews, health examinations, and self-administered questionnaires, with information on socioeconomic position, occupational and leisure time physical activity, physical fitness, body mass index, smoking, alcohol consumption, and physical functional capacity. Analyses included persons who were working and had no limitations in functional capacity at baseline.
The strongest predictor of being physically active at the follow-up was participation in physical activity at baseline, with an OR 13.82 (95%CI 5.50-34.70) for 3 or more types of regular activity, OR 2.33 (95%CI 1.22-4.47) for 1–2 types of regular activity, and OR 3.26 (95%CI 2.07-5.15) for irregular activity, as compared to no activity. Other determinants for being physically active were moving upwards in occupational status, a high level of baseline occupational physical activity and remaining healthy weight during the follow-up.
To prevent physical inactivity among older adults, it is important to promote physical activity already in young adulthood and in middle age and to emphasize the importance of participating in many types of physical activity.
Exercise; Health behavior; Occupation; Prospective studies; Socioeconomic position
Genetic effects contribute to individual differences in smoking behavior. Persistence to smoke despite known harmful health effects is mostly driven by nicotine addiction. As the physiological effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), we aimed at examining whether single nucleotide polymorphisms (SNPs) residing in nAChR subunit (CHRN) genes, other than CHRNA3/CHRNA5/CHRNB4 gene cluster previously showing association in our sample, are associated with smoking quantity or serum cotinine levels.
The study sample consisted of 485 Finnish adult daily smokers (age 30–75 years, 59% men) assessed for the number of cigarettes smoked per day (CPD) and serum cotinine level. We first studied SNPs residing on selected nAChR subunit genes (CHRNA2, CHRNA4, CHRNA6/CHRNB3, CHRNA7, CHRNA9, CHRNA10, CHRNB2, CHRNG/CHRND) genotyped within a genome-wide association study for single SNP and multiple SNP associations by ordinal regression. Next, we explored individual haplotype associations using sliding window technique.
At one of the 8 loci studied, CHRNG/CHRND (chr2), single SNP (rs1190452), multiple SNP, and 2-SNP haplotype analyses (SNPs rs4973539–rs1190452) all showed statistically significant association with cotinine level. The median cotinine levels varied between the 2-SNP haplotypes from 220 ng/ml (AA haplotype) to 249 ng/ml (AG haplotype). We did not observe significant associations with CPD.
These results provide further evidence that the γ−δ nAChR subunit gene region is associated with cotinine levels but not with the number of CPD, illustrating the usefulness of biomarkers in genetic analyses.
Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
Studies investigating the extent to which genetics influences human characteristics such as height have concentrated mainly on common variants of genes, where having one or two copies of a given variant influences the trait or risk of disease. This study explores whether a different type of genetic variant might also be important. We investigate the role of recessive genetic variants, where two identical copies of a variant are required to have an effect. By measuring genome-wide homozygosity—the phenomenon of inheriting two identical copies at a given point of the genome—in 35,000 individuals from 21 European populations, and by comparing this to individual height, we found that the more homozygous the genome, the shorter the individual. The offspring of first cousins (who have increased homozygosity) were predicted to be up to 3 cm shorter on average than the offspring of unrelated parents. Height is influenced by the combined effect of many recessive variants dispersed across the genome. This may also be true for other human characteristics and diseases, opening up a new way to understand how genetic variation influences our health.
We randomised a total of 94 patients with long-standing moderate lumbar spinal stenosis (LSS) into a surgical group and a non-operative group, with 50 and 44 patients, respectively. The operative treatment comprised undercutting laminectomy of stenotic segments, augmented with transpedicular-instrumented fusion in suspected lumbar instability. The primary outcome was the Oswestry disability index (ODI), and the other main outcomes included assessments of leg and back pain and self-reported walking ability, all based on questionnaire data from 85 patients at the 6-year follow-up. At the 6-year follow-up, the mean difference in ODI in favour of surgery was 9.5 (95% confidence interval 0.9–18.1, P-value for global difference 0.006), whereas the intensity of leg or back pain did not differ between the two treatment groups any longer. Walking ability did not differ between the treatment groups at any time. Decompressive surgery of LSS provided modest but consistent improvement in functional ability, surpassing that obtained after non-operative measures.
Spinal stenosis; Surgical treatment; Non-operative treatment; Randomised controlled trial