Background
Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian ...randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one‐second (FEV1) and forced vital capacity (FVC).
Methods
We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI‐associated single nucleotide polymorphisms (SNPs). Results were pooled in meta‐analyses and expressed as odds ratios (ORs) or β‐estimates with 95% confidence interval (CI).
Results
The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI‐increasing allele. The GRS was significantly associated with decrease in FEV1: β=−0.0012 (95% CI: −0.0019, −0.0006) and FVC: β=−0.0022 (95% CI: −0.0031, −0.0014) per BMI‐increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0‐15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0‐24 mL decrease) per 1 kg/m2 higher BMI.
Conclusions
The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and purpose
Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and ...MTA, the genetic background is still not fully established. In a population‐based genome‐wide association study by Chasman et al. (Nat Genet 2011: 43: 695–698), three common variants were found to confer risk of migraine at a genome‐wide significant level (P < 5 × 10−8). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic‐based Danish and Icelandic cohort.
Methods
The top association SNPs were assessed in 2523 cases and 38 170 controls, and a meta‐analysis was performed, combining the discovery set with all the follow‐up studies. Finally the confirmed SNPs were assessed in a genotype–phenotype analysis.
Results
Two out of three SNPs that showed genome‐wide significant associations in the previous study: rs10166942 (near TRPM8) and rs11172113 (in LRP1) were significantly associated with migraine in the present study. The meta‐analysis confirmed the previous three genome‐wide significant associated SNPs (rs2651899, rs10166942 and rs11172113) to confer risk of migraine. In addition, the C‐allele of rs2078371 (near TSPAN‐2) also reached genome‐wide significance for association with migraine OR = 1.14; CI = (1.09–1.20); P = 2.55 × 10−8.
Conclusion
TSPAN‐2 encodes an integral membrane protein involved in oligodendrogenesis. This new finding supports the plausible implication of neuroglia in the pathophysiology of MO and MTA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The well-established link between body fat distribution and metabolic health has been suggested to act through an impact on the remodeling capacity of the adipose tissue. Remodeling of the adipose ...tissue has been shown to affect body fat distribution and might affect the ability to lose weight. We aimed to study the effect of weighted genetic risk scores (GRSs) on weight loss based on single-nucleotide polymorphisms (SNPs) associated with waist-hip-ratio adjusted for body mass index (WHRadjBMI).
We included 707 participants (533 women and 174 men) from the NUGENOB multi-center 10-week diet intervention study with weekly weight measurements. We created 3 GRSs, one including all reported WHRadjBMI SNPs (GRS
), one including only SNPs with genome-wide significance in women or with significantly greater effect in women (GRS
), and one excluding SNPs in the GRS
(GRS
). The data were analyzed in a mixed linear model framework.
The GRS
and GRS
attenuated weight loss in women. The effect was strongest for the GRS
with an effect of 2.21 g per risk allele per day (95% confidence intereval (CI) (0.90;3.52), P=0.0009). Adjustment for WHR, basal metabolic rate or diet compliance did not affect the result. The GRSs had no effect on weight loss in men. The VEGFA rs1358980-T strongly attenuated weight loss in both men and women (β=15.95 g per risk allele per day, (3.16;26.74), P=0.013) and (β=15.95 g per risk allele per day, (2.58;13.53), P=0.004), respectively).
Our findings suggest that genetic variants influencing body fat distribution attenuate weight loss in women independently on the effect on WHR. The stronger effect of the GRS
implies heterogenic effects of the WHRadjBMI variants on weight loss. A strong effect of rs1358980-T in the VEGFA locus suggests that angiogenesis plays a role, but this needs confirmation from functional studies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background In Europeans, 45 genetic risk variants for coronary artery disease (CAD) have been identified in genome-wide association studies. We constructed a genetic risk score (GRS) of ...these variants to estimate the effect on incidence and clinical predictability of myocardial infarction (MI) and CAD. Methods Genotype was available from 6041 Danes. An unweighted GRS was constructed by making a summated score of the 45 known genetic CAD risk variants. Registries provided information (mean follow-up = 11.6 years) on CAD (n = 374) and MI (n = 124) events. Cox proportional hazard estimates with age as time scale was adjusted for sex, BMI, type 2 diabetes mellitus and smoking status. Analyses were also stratified either by sex or median age (below or above 45 years of age). We estimated GRS contribution to MI prediction by assessing net reclassification index (NRI) and integrated discrimination improvement (IDI) added to the European SCORE for 10-year MI risk prediction. Results The GRS associated significantly with risk of incident MI (allele-dependent hazard ratio (95%CI): 1.06 (1.02–1.11), p = 0.01) but not with CAD ( p = 0.39). Stratification revealed association of GRS with MI in men (1.06 (1.01–1.12), p = 0.02) and in individuals above the median of 45.11 years of age (1.06 (1.00–1.12), p = 0.03). There was no interaction between GRS and gender ( p = 0.90) or age ( p = 0.83). The GRS improved neither NRI nor IDI. Conclusion The GRS of 45 GWAS identified risk variants increase the risk of MI in a Danish cohort. The GRS did not improve NRI or IDI beyond the performance of conventional European SCORE risk factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UPCLJ, UPUK
Aims/hypothesis A meta-analysis of 21 genome-wide association studies identified 11 novel genetic loci implicated in fasting glucose homeostasis. We aimed to evaluate the impact of these variants on ...insulin release and insulin sensitivity estimated from OGTTs. Methods Eleven variants in or near DGKB/TMEM195, ADCY5, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B and IGF1 were genotyped in 6,784 middle-aged participants of the population-based Inter99 cohort. Association studies of quantitative estimates of insulin release and insulin sensitivity were performed in 5,722 non-diabetic Danish participants on whom an OGTT was performed. Results Assuming an additive genetic model, carriers of the alleles increasing fasting glucose in DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B showed decreased glucose-stimulated insulin release as assessed by the BIGTT-acute insulin response index (2.7-3.5%; p < 0.005 for all) and by corrected insulin response (2.8-5.9%; p < 0.03 for all). In addition, the PROX1 glucose-raising allele showed a 2.9% decreased corrected insulin response (p = 0.03), while the hyperglycaemic allele of variants in or near ADRA2A, FADS1, CRY2 and C2CD4B were associated with a 2.6% to 9.3% decrease in one or both of two different OGTT-based disposition indices (p < 0.02 for all). After correction for multiple testing, variants in the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with estimates of beta cell function. Conclusions/interpretation We found that the lead variants at the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response. This association underlines the importance of pancreatic beta cell dysfunction in the genetic predisposition to hyperglycaemia and type 2 diabetes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor alpha subunit. This inhibition is enhanced by the minor Q allele of the K121Q ...polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes.
The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.
No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 95% CI 1.10-1.25, p=1x10(-6)). In case-control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m(2); odds ratio 1.63 95% CI 1.09-2.46, p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait.
In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Observational studies have suggested low serum levels of vitamin B12 or folate to be risk factors of depression and anxiety. However, these results may be biased by confounding and reverse causation. ...Mendelian randomization studies are not subject to these limitations. The aim was to examine the association of genetic scores of vitamin B12 and folate-associated alleles with depression and anxiety.
The study included 4126 participants from two Danish population-based studies. Serum vitamin B12 and folate were measured. Weighed allele scores were calculated as the sum of weights (genetic effect sizes) for 12 and two variants increasing circulating levels of vitamin B12 and folate, respectively. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety.
An increased weighed allele score for serum vitamin B12 was associated with decreased odds of a SCL-90-R score above the 90th percentile (OR 0.540 (95%CI 0.302-0.967)) in Health2006 but not in Inter99, in the pooled analysis (OR 0.817 (95%CI 0.331-2.018)) or with other outcomes. The weighed allele score for serum folate was not associated with any of the measured outcome variables: SCL-90-R scores of depression (pooled OR 0.603 (95%CI 0.101-3.602)), anxiety (pooled OR 0.619 (95%CI 0.110-3.495)), combined score or history of doctor-diagnosed depression or anxiety.
Our results do not provide evidence for a causal effect of circulating folate or vitamin B12 on the risk of depression or anxiety. However, we cannot rule out small to moderate effects, and thus large scale studies are needed.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Aims/hypothesis A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was ...replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits. Methods We genotyped the rs7172432 variant in the population-based Inter99 cohort (n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT. Results The diabetes-associated A allele was associated with 0.60 cm higher waist circumference (p = 0.004), 0.037 mmol/l higher fasting plasma glucose (p = 4 × 10⁻⁵) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT (p = 4 × 10⁻⁴). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin (β = −0.039, p = 2 × 10⁻⁷), insulinogenic index (β = −0.057, p = 1 × 10⁻⁸) and BIGTT-acute insulin release (β = −0.041, p = 9 × 10⁻⁹). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 (R ² < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305. Conclusions/interpretation The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims/hypothesis The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined ...associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. Methods Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. Results Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β = −33 g 95% CI −55, −10, p = 0.004) and CDKAL1 rs7756992 (β = −22 g 95% CI −43, −1, p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (β = −20 g 95% CI −29, −11, p = 5 × 10⁻⁶). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (β = −16 g 95% CI −24, −8, p = 8 × 10⁻⁵). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β = −35 g 95% CI −69, −2, p = 0.037). Conclusions/interpretation We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The aim was to examine the association of genetic risk scores (GRSs) of vitamin B12 and folate-associated variants with blood pressure and lipids.
The study included 12 532 adults from three ...population-based studies (Inter99, Health2006 and Dan-MONICA10) conducted in Denmark. GRSs were calculated by summarising the number of vitamin B12 and folate increasing alleles. Weighted GRSs were calculated as the sum of weights for each allele corresponding to genetic effects sizes.
GRSs for serum vitamin B12 and folate were associated with serum vitamin B12 and folate, respectively. The β coefficients (95% confidence interval (CI), P-value) for regression of log-transformed serum B12/folate on the weighted GRSs were 0.57 (0.54, 0.61), P<0.001 and 0.85 (0.70, 1.01), P<0.01. No associations were observed between the vitamin B12 GRSs and any of the blood pressure and lipid-related outcomes in the combined analyses. Increasing number of folate increasing alleles was associated with increased high-density lipoprotein (HDL) cholesterol concentrations (β coefficient (95% CI, P-value) for regression of log-transformed HDL on the weighted GRSs, 0.081 (0.015, 0.148), P=0.017), but not with blood pressure, triglyceride, and low-density lipoprotein and total cholesterol levels.
GRSs were not associated with blood pressure and lipid levels, except for an association between the GRS for folate and HDL cholesterol. Further studies are needed to determine whether a causal association between folate and HDL cholesterol exists.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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