Cohort Profile Update: The HUNT Study, Norway Åsvold, Bjørn Olav; Langhammer, Arnulf; Rehn, Tommy Aune ...
International journal of epidemiology,
02/2023, Letnik:
52, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In the HUNT Study, all residents aged ≥20 years in the Nord-Trøndelag region, Norway, have been invited to repeated surveys since 1984-86. The study data may be linked to local and national health ...registries.
The HUNT4 survey in 2017-19 included 56 042 participants in Nord-Trøndelag and 107 711 participants in the neighbouring Sør-Trøndelag region.
The HUNT4 data enable more long-term follow-up, studies of life course health trajectories and within-family studies.
New measures include body composition analysis using bioelectrical impedance; a 1-week accelerometer recording; physical and cognitive testing in older adults; measurements of haemoglobin and blood cell counts, HbA1c and phosphatidylethanol; and genotyping.
Researchers can apply for HUNT data access from HUNT Research Centre if they have obtained project approval from the Regional Committee for Medical and Health Research Ethics, see www.ntnu.edu/hunt/data.
There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis ...posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.
Low cardiorespiratory fitness (CRF) is a major risk factor for cardiovascular disease (CVD) and a stronger predictor of CVD morbidity and mortality than established risk factors. The genetic ...component of CRF, quantified as peak oxygen uptake (V̇O 2peak ), is estimated to be ~60%. Unfortunately, current studies on genetic markers for CRF have been limited by small sample sizes and using estimated CRF. To overcome these limitations, we performed a large-scale systematic screening for genetic variants associated with V̇O 2peak .
A genome-wide association study was performed with BOLT-LMM including directly measured V̇O 2peak from 4525 participants in the HUNT3 Fitness study and 14 million single-nucleotide polymorphisms (SNP). For validation, similar analyses were performed in the United Kingdom Biobank (UKB), where CRF was assessed through a submaximal bicycle test, including ~60,000 participants and ~60 million SNP. Functional mapping and annotation of the genome-wide association study results was conducted using FUMA.
In HUNT, two genome-wide significant SNP associated with V̇O 2peak were identified in the total population, two in males, and 35 in females. Two SNP in the female population showed nominally significant association in the UKB. One of the replicated SNP is located in PIK3R5 , shown to be of importance for cardiac function and CVD. Bioinformatic analyses of the total and male population revealed candidate SNP in PPP3CA , previously associated with CRF.
We identified 38 novel SNP associated with V̇O 2peak in HUNT. Two SNP were nominally replicated in UKB. Several interesting genes emerged from the functional analyses, among them one previously reported to be associated with CVD and another with CRF.
In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the ...other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI.
We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study HUNT), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered.
Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the "obesity paradox," where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we ...found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.
Previous studies of associations of forced expiratory lung volume in one second (FEV.sub.1) with peak oxygen uptake (VO.sub.2peak) in chronic obstructive pulmonary disease (COPD) have not taken sex, ...age and height related variance of dynamic lung volumes into account. Nor have such demographic spread of spirometric measures been considered in studies comparing VO.sub.2peak between COPD phenotypes characterized by degree of emphysema. We aimed to assess the association of FEV.sub.1Z-score with VO.sub.2peak in COPD (n = 186) and investigate whether this association differs between emphysema (E-COPD) and non-emphysema (NE-COPD) phenotypes. Corresponding assessments using standardized percent predicted FEV.sub.1 (ppFEV.sub.1) were performed for comparison. Additionally, phenotype related differences in VO.sub.2peak were compared using FEV.sub.1Z-score and ppFEV.sub.1 as alternative expressions of FEV.sub.1 . E-COPD and NE-COPD were defined by transfer factor of the lung for carbon monoxide below and above lower limits of normal (LLN), respectively. The associations were assessed in linear regression models. One unit reduction in FEV.sub.1Z-score was associated with 1.9 (95% CI 1.4, 2.5) ml/kg/min lower VO.sub.2peak . In stratified analyses, corresponding estimates were 2.2 (95% CI 1.4, 2.9) and 1.2 (95% CI 0.2, 2.2) ml/kg/min lower VO.sub.2peak in E-COPD and NE-COPD, respectively. The association did not differ statistically by COPD phenotype (p-value for interaction = 0.153). Similar estimates were obtained in analyses using standardized ppFEV.sub.1 . Compared to NE-COPD, VO.sub.2peak was 2.2 (95% CI 0.8, 3.6) and 2.1 (95% CI 0.8, 3.5) ml/kg/min lower in E-COPD when adjusted for FEV.sub.1Z-score and ppFEV.sub.1, respectively. In COPD, FEV.sub.1Z-score is positively associated with VO.sub.2peak . This association was stronger in E-COPD but did not differ statistically by phenotype. Both the association of FEV.sub.1 with VO.sub.2peak and the difference in VO.sub.2peak comparing COPD phenotypes seems independent of sex, age and height related variance in FEV.sub.1 . Mechanisms leading to reduction in FEV.sub.1 may contribute to lower VO.sub.2peak in E-COPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Aims
A low resting heart rate (RHR) implies a more efficient heart function and a lower risk of cardiovascular disease. However, observational studies have reported a U-shaped association ...between RHR and atrial fibrillation (AF). In contrast, Mendelian randomization (MR) studies have found an inverse causal association between RHR and AF. Hence, the causal nature of the relationship is not clear. The aim is to investigate the causal association and its shape between RHR on AF using linear and non-linear MR (NLMR).
Methods and results
Linear and non-linear MR were performed on individual-level data in the Trøndelag Health Study (HUNT) and UK Biobank (UKB). HUNT consists of 69 155 individuals with 7,062 AF cases, while UKB provides data on 431 852 individuals with 20 452 AF cases. The linear MR found an inverse relationship between RHR and AF with an OR = 0.95 95% confidence interval (CI): 0.93–0.98 and OR = 0.96 (95% CI: 0.95–0.97) per unit decrease in RHR in HUNT and UKB, respectively. The NLMR was supportive of an inverse linear relationship in both HUNT and UKB for RHR values <90 beats per minute (bpm). Several sensitivity analyses were also consistent.
Conclusion
In contrast with the current observational knowledge of RHR and AF, an inverse causal association between RHR and AF was demonstrated in both linear and non-linear MR for RHR values up to 90 bpm. Further exploring the underlying mechanisms of the genetic instrument for RHR may shed light on whether pleiotropy is biasing this association.
Graphical Abstract
Graphical abstract
Alzheimer's disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 ...participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.
Abstract
Background
The proportion of venous thromboembolism (VTE) events that can be attributed to established prothrombotic genotypes has been scarcely investigated in the general population. We ...aimed to estimate the proportion of VTEs in the population that could be attributed to established prothrombotic genotypes using a population-based case-cohort.
Methods
Cases with incident VTE (
n
= 1,493) and a randomly sampled subcohort (
n
= 13,069) were derived from the Tromsø Study (1994–2012) and the Nord-Trøndelag Health (HUNT) study (1995–2008). DNA samples were genotyped for 17 single-nucleotide polymorphisms (SNPs) associated with VTE. Hazard ratios with 95% confidence intervals (CIs) were estimated in Cox regression models. Population-attributable fractions (PAFs) with 95% bias-corrected CIs (based on 10,000 bootstrap samples) were estimated using a cumulative model where SNPs significantly associated with VTE were added one by one in ranked order of the individual PAFs.
Results
Six SNPs were significantly associated with VTE (rs1799963 Prothrombin, rs2066865 FGG, rs6025 FV Leiden, rs2289252 F11, rs2036914 F11, and rs8176719 ABO). The cumulative PAF for the six-SNP model was 45.3% (95% CI: 19.7–71.6) for total VTE and 61.7% (95% CI: 19.6–89.3) for unprovoked VTE. The PAF for prothrombotic genotypes was higher for deep vein thrombosis (DVT; 52.9%) than for PE (33.8%), and higher for those aged <70 years (66.1%) than for those aged ≥70 years (24.9%).
Conclusion
Our findings suggest that 45 to 62% of all VTE events in the population can be attributed to known prothrombotic genotypes. The PAF of established prothrombotic genotypes was higher in DVT than in PE, and higher in the young than in the elderly.
Observational epidemiological studies have reported that higher maternal blood pressure (BP) during pregnancy is associated with increased future risk of offspring cardiometabolic disease. However, ...it is unclear whether this association represents a causal relationship through intrauterine mechanisms. We used a Mendelian randomization (MR) framework to examine the relationship between unweighted maternal genetic scores for systolic BP and diastolic BP and a range of cardiometabolic risk factors in the offspring of up to 29 708 genotyped mother-offspring pairs from the UKB study (UK Biobank) and the HUNT study (Trøndelag Health). We conducted similar analyses in up to 21 423 father-offspring pairs from the same cohorts. We confirmed that the BP-associated genetic variants from the general population sample also had similar effects on maternal BP during pregnancy in independent cohorts. We did not detect any association between maternal (or paternal) unweighted genetic scores and cardiometabolic offspring outcomes in the meta-analysis of UKB and HUNT after adjusting for offspring genotypes at the same loci. We find little evidence to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life.
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