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1.  Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity 
Human Molecular Genetics  2013;22(13):2735-2747.
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10−8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
doi:10.1093/hmg/ddt104
PMCID: PMC3674797  PMID: 23449627
2.  Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake1234 
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
doi:10.3945/ajcn.112.052183
PMCID: PMC3652928  PMID: 23636237
3.  Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque 
Scientific Reports  2014;4:4650.
Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.
doi:10.1038/srep04650
PMCID: PMC3983598  PMID: 24722012
4.  Determinants of exercise peak arterial blood pressure, circulatory power, and exercise cardiac power in a population based sample of Finnish male and female aged 30 to 47 years: the Cardiovascular Risk in Young Finns Study 
Background
Novel parameters derived from peak maximal oxygen uptake (VO2) and exercise arterial blood pressure, such as peak circulatory power (CP) and exercise cardiac power (ECP), can be used in the risk assessment of cardiovascular disease and stroke. However, the determinants of these factors are poorly characterized in the general population.
Methods
We assessed peak arterial blood pressure, CP and ECP with standardized cardiopulmonary exercise test (CPET) on 281 female and 257 male participants of the Cardiovascular Risk in Young Finns Study. The subjects were aged 30–47 years. Peak VO2 as well as systolic and diastolic arterial blood pressures were measured to calculate peak mean arterial pressure, CP and ECP. These parameters were assessed for correlation with sex, age, height, weight, waist-to-hip ratio, smoking, physical activity index (PAI), fasting insulin and glucose levels as well as the use of antihypertensive treatment.
Results
Sex, age and weight explained 36% of the variation in peak systolic blood pressure, and these factors in combination with height and the use of antihypertensive treatment explained 13% of the variation in peak diastolic blood pressure. Sex, height, weight, waist-to-hip ratio, PAI and smoking explained 49% − 52% of the variation in peak CP. Sex, age, height, weight, waist-to-hip ratio, PAI, smoking and insulin levels explained 21% − 49% of variation in ECP.
Conclusions
Subject demographics and lifestyle-related factors should be taken into account when exercise blood pressure response, CP and ECP are used to evaluate patients’ cardiac function in CPET.
doi:10.1186/1471-2261-14-35
PMCID: PMC3995605  PMID: 24621399
Aerobic capacity; Peak oxygen consumption; Population; Cardiopulmonary exercise test; Oxygen pulse; Circulatory power; Exercise cardiac power; Blood pressure
5.  Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults 
Diabetes Care  2013;36(3):648-655.
OBJECTIVE
Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults.
RESEARCH DESIGN AND METHODS
Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood.
RESULTS
Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination.
CONCLUSIONS
Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.
doi:10.2337/dc12-0895
PMCID: PMC3579331  PMID: 23129134
6.  Cohort Profile: The International Childhood Cardiovascular Cohort (i3C) Consortium 
This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence.
doi:10.1093/ije/dys004
PMCID: PMC3600617  PMID: 22434861
7.  Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts 
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
doi:10.1093/aje/kws297
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
8.  Maintenance of genetic variation in human personality: Testing evolutionary models by estimating heritability due to common causal variants and investigating the effect of distant inbreeding 
Personality traits are basic dimensions of behavioural variation, and twin, family, and adoption studies show that around 30% of the between-individual variation is due to genetic variation. There is rapidly-growing interest in understanding the evolutionary basis of this genetic variation. Several evolutionary mechanisms could explain how genetic variation is maintained in traits, and each of these makes predictions in terms of the relative contribution of rare and common genetic variants to personality variation, the magnitude of nonadditive genetic influences, and whether personality is affected by inbreeding. Using genome-wide SNP data from >8,000 individuals, we estimated that little variation in the Cloninger personality dimensions (7.2% on average) is due to the combined effect of common, additive genetic variants across the genome, suggesting that most heritable variation in personality is due to rare variant effects and/or a combination of dominance and epistasis. Furthermore, higher levels of inbreeding were associated with less socially-desirable personality trait levels in three of the four personality dimensions. These findings are consistent with genetic variation in personality traits having been maintained by mutation-selection balance.
doi:10.1111/j.1558-5646.2012.01679.x
PMCID: PMC3518920  PMID: 23025612
balancing selection; mutation-selection balance; antagonistic pleiotropy; correlational selection; neutral; trade-offs; personality; temperament; mutation; evolution; behavioural syndromes
9.  A Meta-Analysis of Genome-Wide Association Studies of the Electrocardiographic Early Repolarization Pattern 
Background
The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable and mutations have been described in syndromatic cases.
Objective
To conduct a meta-analysis of genome-wide association studies (GWAS) to identify common genetic variants influencing ERP.
Methods
We ascertained ERP based on electrocardiograms in three large community-based cohorts from Europe and the US: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed GWAS in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached p≤1×10−5 in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.
Results
Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9±8.9 years, 30.3% women; ERP negative: 47.5±9.4 years, 54.2% women). After meta-analysis, eight single nucleotide polymorphisms reached p≤1×10−5: The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36–0.61; p=6.9×10−9). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25–1.69; p=8.5×10−7). In the replication step (7151 individuals), none of the eight variants replicated, and combined meta-analysis results failed to reach genome-wide significance.
Conclusions
In a GWAS, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
doi:10.1016/j.hrthm.2012.06.008
PMCID: PMC3459269  PMID: 22683750
Early repolarization; Sudden cardiac death; Arrhythmia; GWAS; Meta-analysis; Electrocardiogram
10.  Childhood Nutrition in Predicting Metabolic Syndrome in Adults 
Diabetes Care  2012;35(9):1937-1943.
OBJECTIVE
Our aim was to study the associations of childhood lifestyle factors (the frequency of consumption of vegetables, fruit, fish, and meat, butter use on bread, and physical activity) with the metabolic syndrome (MetS) in adulthood.
RESEARCH DESIGN AND METHODS
The study cohort consisted of 2,128 individuals, 3–18 years of age at the baseline, with a follow-up time of 27 years. We used the average of lifestyle factor measurements taken in 1980, 1983, and 1986 in the analyses. Childhood dietary factors and physical activity were assessed by self-reported questionnaires, and a harmonized definition of MetS was used as the adult outcome.
RESULTS
Childhood vegetable consumption frequency was inversely associated with adult MetS (odds ratio [OR] 0.86 [95% CI 0.77–0.97], P = 0.02) in a multivariable analysis adjusted with age, sex, childhood metabolic risk factors (lipids, systolic blood pressure, insulin, BMI, and C-reactive protein), family history of type 2 diabetes and hypertension, and socioeconomic status. The association remained even after adjustment for adulthood vegetable consumption. Associations with the other childhood lifestyle factors were not found. Of the individual components of MetS, decreased frequency of childhood vegetable consumption predicted high blood pressure (0.88 [0.80–0.98], P = 0.01) and a high triglyceride value (0.88 [0.79–0.99], P = 0.03) after adjustment for the above-mentioned risk factors.
CONCLUSIONS
Childhood vegetable consumption frequency is inversely associated with MetS in adulthood. Our findings suggest that a higher intake of vegetables in childhood may have a protective effect on MetS in adulthood.
doi:10.2337/dc12-0019
PMCID: PMC3425009  PMID: 22815293
11.  Effects of sea buckthorn and bilberry on serum metabolites differ according to baseline metabolic profiles in overweight women: a randomized crossover trial1234 
Background: Berries are associated with health benefits. Little is known about the effect of baseline metabolome on the overall metabolic responses to berry intake.
Objective: We studied the effects of berries on serum metabolome.
Design: Eighty overweight women completed this randomized crossover study. During the interventions of 30 d, subjects consumed dried sea buckthorn berries (SBs), sea buckthorn oil (SBo), sea buckthorn phenolics ethanol extract mixed with maltodextrin (SBe+MD) (1:1), or frozen bilberries. Metabolic profiles were quantified from serum samples by using 1H nuclear magnetic resonance spectroscopy.
Results: All interventions induced a significant (P < 0.001–0.003) effect on the overall metabolic profiles. The effect was observed both in participants who had a metabolic profile that reflected higher cardiometabolic risk at baseline (group B: P = 0.001–0.008) and in participants who had a lower-risk profile (group A: P < 0.001–0.009). Although most of the changes in individual metabolites were not statistically significant after correction for multiplicity, clear trends were observed. SB-induced effects were mainly on serum triglycerides and very-low-density lipoprotein (VLDL) and its subclasses, which decreased in metabolic group B. SBo induced a decreasing trend in serum total, intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) cholesterol and subfractions of IDL and LDL in group B. During the SBe+MD treatment, VLDL fractions and serum triglycerides increased. Bilberries caused beneficial changes in serum lipids and lipoproteins in group B, whereas the opposite was true in group A.
Conclusion: Berry intake has overall metabolic effects, which depend on the cardiometabolic risk profile at baseline. This trial was registered at clinicaltrials.gov as NCT01860547.
doi:10.3945/ajcn.113.060590
PMCID: PMC3778864  PMID: 23945716
12.  Starting bedtime glargine versus NPH insulin in poorly controlled type 2 diabetic patients with various hyperglycemia types (fasting type or postprandial type) 
Acta Diabetologica  2013;51:233-238.
Our aim was to compare the effects of an intermediate acting human insulin (NPH) and a long-acting insulin analog, insulin glargine, in insulin naïve type 2 diabetes patients, stratified by the type of hyperglycemia (fasting or postprandial type). Based on different action profiles, we hypothesized that patients having different hyperglycemia types would react differently when treated with these insulins. This is a post hoc analysis of the Lanmet study data. The Lanmet study was a randomized, 36-week controlled insulin initiation study in type 2 diabetes patients. 109 subjects with baseline HbA1c >8.0 % (64 mmol/mol) completed the study. The patients were divided into two groups according to fasting glucose (mmol/l)/HbA1c (%) ratio. Patients with a ratio ≥1.3 were defined as having fasting type and those with a ratio <1.3 as having postprandial type hyperglycemia. The main outcome measures were change in HbA1c and body weight, and final insulin dose. Independently of insulin type, compared to patients with postprandial type hyperglycemia, those with fasting type hyperglycemia had 2.1 kg/m2 greater initial BMI (p = 0.044), gained 2.0 kg more weight (p = 0.020, adjusted for baseline BMI p = 0.035), and had 36 % greater final insulin dose/kg (p = 0.001). With respect to hyperglycemia type, there was no difference between NPH and glargine in their effects on HbA1c. When starting bedtime insulin in type 2 diabetes patients, those with fasting type hyperglycemia are prone to greater weight gain. Hyperglycemia type does not help in identifying patients who would benefit specially from either NPH insulin or insulin glargine.
doi:10.1007/s00592-013-0505-7
PMCID: PMC3969512  PMID: 23880900
Insulin treatment; Insulin analog; Hyperglycemia type; Body weight increase; Type 2 diabetes
13.  Metabolic Signatures of Insulin Resistance in 7,098 Young Adults 
Diabetes  2012;61(6):1372-1380.
Metabolite associations with insulin resistance were studied in 7,098 young Finns (age 31 ± 3 years; 52% women) to elucidate underlying metabolic pathways. Insulin resistance was assessed by the homeostasis model (HOMA-IR) and circulating metabolites quantified by high-throughput nuclear magnetic resonance spectroscopy in two population-based cohorts. Associations were analyzed using regression models adjusted for age, waist, and standard lipids. Branched-chain and aromatic amino acids, gluconeogenesis intermediates, ketone bodies, and fatty acid composition and saturation were associated with HOMA-IR (P < 0.0005 for 20 metabolite measures). Leu, Ile, Val, and Tyr displayed sex- and obesity-dependent interactions, with associations being significant for women only if they were abdominally obese. Origins of fasting metabolite levels were studied with dietary and physical activity data. Here, protein energy intake was associated with Val, Phe, Tyr, and Gln but not insulin resistance index. We further tested if 12 genetic variants regulating the metabolites also contributed to insulin resistance. The genetic determinants of metabolite levels were not associated with HOMA-IR, with the exception of a variant in GCKR associated with 12 metabolites, including amino acids (P < 0.0005). Nonetheless, metabolic signatures extending beyond obesity and lipid abnormalities reflected the degree of insulin resistance evidenced in young, normoglycemic adults with sex-specific fingerprints.
doi:10.2337/db11-1355
PMCID: PMC3357275  PMID: 22511205
14.  Ideal Cardiovascular Health in Young Adult Populations From the United States, Finland, and Australia and Its Association With cIMT: The International Childhood Cardiovascular Cohort Consortium 
Background
Goals for cardiovascular (CV) disease prevention were set by the American Heart Association in 2010 for the concept of CV health. Ideal CV health is defined by 7 CV health metrics: blood pressure, glucose, cholesterol, body mass index, and physical activity on recommended levels; nonsmoking; and a healthy diet. We studied the prevalence of ideal CV health and its associations with ultrasonographically measured carotid intima‐media thickness (cIMT) cross‐sectionally in 5 international populations.
Methods and Results
Prevalence of ideal CV health was assessed among 5785 young adults (age, 36.6±3.2 years) comprising 335 participants from the Minneapolis Childhood Cohort Studies (Minnesota), 723 from the Princeton Follow‐up Study, 981 from the Bogalusa Heart Study (BHS), 1898 from the Cardiovascular Risk in Young Finns Study (YFS), and 1848 from the Childhood Determinants of Adult Health Study (CDAH). Only 1% of the participants had all 7 ideal CV health metrics. The number of ideal CV health metrics associated inversely with cIMT in the 4 cohorts in which cIMT was available: for each additional ideal CV health metric, cIMT was 12.7 μm thinner in Minnesota (P=0.0002), 9.1 μm thinner in BHS (P=0.05), 10.4 μm thinner in YFS (P<0.0001), and 3.4 μm thinner in CDAH (P=0.03).
Conclusions
The number of ideal CV health metrics was inversely associated with cIMT in the cohorts in which cIMT was available, indicating that ideal CV health metrics are associated with vascular health at the population level. Ideal CV health was rare in this large international sample of young adults, emphasizing the need for effective strategies for health promotion.
doi:10.1161/JAHA.113.000244
PMCID: PMC3698791  PMID: 23782922
cardiovascular; carotid intima‐media thickness; cohort studies; health behavior
15.  Genome-wide association study identifies multiple loci influencing human serum metabolite levels 
Nature genetics  2012;44(3):269-276.
Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.
doi:10.1038/ng.1073
PMCID: PMC3605033  PMID: 22286219
16.  Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure 
PLoS Genetics  2013;9(2):e1003247.
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Author Summary
Osteoporosis is a common highly heritable skeletal disease characterized by reduced bone mineral density (BMD) and deteriorated bone microstructure, resulting in an increased risk of fracture. Most previous genetic epidemiology studies have focused on the genetics of the complex trait BMD, not being able to separate genetic determinants of the trabecular and cortical bone compartments and bone microstructure. The trabecular and cortical BMDs can be analysed separately by computed tomography. Therefore, we performed separate genome-wide association studies for trabecular and cortical BMDs, demonstrating that the genetic determinants of cortical and trabecular BMDs differ. Genetic variants in the RANKL, LOC285735, OPG, and ESR1 loci were associated with cortical BMD, while a genetic variant in the FMN2/GREM2 locus was associated with trabecular BMD. Two of these are novel bone-related loci. Follow-up analyses of bone microstructure demonstrated that a genetic variant in the RANKL locus is associated with cortical porosity and that the FMN2/GREM2 locus is associated with trabecular number and thickness. We propose that a genetic variant in the RANKL locus influences cortical BMD via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences trabecular BMD and fracture risk via effects on both trabecular number and thickness.
doi:10.1371/journal.pgen.1003247
PMCID: PMC3578773  PMID: 23437003
17.  Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts 
PLoS Medicine  2013;10(2):e1001383.
A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Background
Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
Methods and Findings
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects.
Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
Conclusions
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements.
Why Was This Study Done?
Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations.
What Did the Researchers Do and Find?
The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium.
What Do These Findings Mean?
These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383.
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population
The World Health Organization provides information on obesity (in several languages)
The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D
The International Obesity Taskforce provides information about the global obesity epidemic
The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish)
MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits
doi:10.1371/journal.pmed.1001383
PMCID: PMC3564800  PMID: 23393431
18.  GENETIC VARIANTS AND BLOOD PRESSURE IN A POPULATION-BASED COHORT: THE CARDIOVASCULAR RISK IN YOUNG FINNS STUDY 
Hypertension  2011;58(6):1079-1085.
Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2,357). Blood pressure was measured at baseline in 1980 (age 3–18 years) and in follow-ups in 1983, 1986, 2001 and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped and three genetic risk scores associated with systolic and diastolic blood pressure and their combination were derived for all participants. Effects of the genetic risk score were 0.47 mmHg for systolic and 0.53 mmHg for diastolic blood pressure (both p<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 onwards (β=0.68 mmHg, p=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (p<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood, individuals with several susceptibility alleles have on average a 0.5 mmHg higher blood pressure and this trajectory continues from childhood to adulthood.
doi:10.1161/HYPERTENSIONAHA.111.179291
PMCID: PMC3247907  PMID: 22025373
Epidemiological study; Genetic risk score; Blood Pressure; Cardiovascular disease
19.  Pairwise Measures of Causal Direction in the Epidemiology of Sleep Problems and Depression 
PLoS ONE  2012;7(11):e50841.
Depressive mood is often preceded by sleep problems, suggesting that they increase the risk of depression. Sleep problems can also reflect prodromal symptom of depression, thus temporal precedence alone is insufficient to confirm causality. The authors applied recently introduced statistical causal-discovery algorithms that can estimate causality from cross-sectional samples in order to infer the direction of causality between the two sets of symptoms from a novel perspective. Two common-population samples were used; one from the Young Finns study (690 men and 997 women, average age 37.7 years, range 30–45), and another from the Wisconsin Longitudinal study (3101 men and 3539 women, average age 53.1 years, range 52–55). These included three depression questionnaires (two in Young Finns data) and two sleep problem questionnaires. Three different causality estimates were constructed for each data set, tested in a benchmark data with a (practically) known causality, and tested for assumption violations using simulated data. Causality algorithms performed well in the benchmark data and simulations, and a prediction was drawn for future empirical studies to confirm: for minor depression/dysphoria, sleep problems cause significantly more dysphoria than dysphoria causes sleep problems. The situation may change as depression becomes more severe, or more severe levels of symptoms are evaluated; also, artefacts due to severe depression being less well presented in the population data than minor depression may intervene the estimation for depression scales that emphasize severe symptoms. The findings are consistent with other emerging epidemiological and biological evidence.
doi:10.1371/journal.pone.0050841
PMCID: PMC3511346  PMID: 23226400
20.  Selenium Status and Blood Lipids: The Cardiovascular Risk in Young Finns Study 
Journal of internal medicine  2011;270(5):469-477.
Background
Concern has been recently raised about possible adverse cardio-metabolic effects of high selenium status, such as increased risks of diabetes and hyperlipidemia. However, most of the evidence comes from selenium-replete populations such as the US.
Objectives
To examine cross-sectional and longitudinal associations of serum selenium with cardiovascular risk factors in Finland where selenium levels were among the lowest in the world until the early 1980s before the implementation of a nationwide selenium fertilization program.
Methods
Serum selenium was measured in 1,235 young Finns aged 3-18 years at baseline in 1980 (pre-fertilization), and in a subgroup (N=262) at the 6-year follow-up (1986, post-fertilization). During the 27-year follow-up, serum lipids, blood pressure, BMI, and smoking were assessed five times (1980, 1983, 1986, 2001, and 2007).
Results
Mean (±SD) serum selenium concentrations were 74.3±14.0 ng/mL in 1980 and 106.6±12.5 ng/mL in 1986 (average increase 32.3 ng/mL; 95% CI: 30.3 to 34.3, p<0.0001). In univariate and multivariable cross-sectional models in 1980 and 1986, increased serum selenium levels were consistently associated with increased total, HDL- and LDL-cholesterol. However, the average longitudinal changes in lipids were −0.20 mmol/L (95% CI: −0.30 to −0.10, p<0.0001) for total cholesterol, 0.06 mmol/L (95% CI: 0.03 to 0.10, p<0.0001) for HDL-cholesterol, and −0.23 mmol/L (95% CI: −0.31 to −0.14, p<0.0001) for LDL-cholesterol. Selenium measured in 1986 was not associated with lipids assessed in 2001 and 2007.
Conclusions
Cross-sectional findings from the Young Finns study corroborate positive associations of selenium status with serum lipids. However, longitudinal evidence does not support the causality of this link.
doi:10.1111/j.1365-2796.2011.02398.x
PMCID: PMC3172343  PMID: 21554435
cardiovascular; cross-sectional; follow-up; lipids; risk factors; selenium
21.  Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution but No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits 
Background
Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS.
Methods and Results
A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status.
Conclusions
Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance.
doi:10.1161/CIRCGENETICS.111.961482
PMCID: PMC3378651  PMID: 22399527
metabolic syndrome; risk factors; genome-wide association study; meta-analysis; lipids
22.  Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA 
PLoS ONE  2012;7(9):e44008.
Rationale
Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.
Objectives
To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.
Methods
The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.
Main Results
We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.
Conclusions
Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
doi:10.1371/journal.pone.0044008
PMCID: PMC3461045  PMID: 23028483
23.  Preconception cardiovascular risk factors and pregnancy outcome 
Epidemiology (Cambridge, Mass.)  2011;22(5):724-730.
Background
Pregnancy-related cardiovascular conditions are associated with both poorer pregnancy outcomes and cardiovascular disease later in life. Little is known about the relationship between preconception cardiovascular risk factor levels and pregnancy complications.
Methods
Data from the Cardiovascular Risk in Young Finns Study were linked with birth registry data for 1142 primiparous women. Age-standardized levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, insulin, and glucose from the study visit prior to last menstrual period were calculated. These factors were examined as predictors of gestational age, preterm birth (<37 weeks), birthweight, low birthweight (<2500 g), small-for-gestational-age (weight <10th percentile for gestational age), hypertensive disorders of pregnancy, and gestational diabetes, using linear and Poisson regression with adjustment for age, body mass index, smoking, and socioeconomic status.
Results
Higher triglycerides were associated with a higher risk of hypertensive disorders (adjusted risk ratio [aRR]= 1.42 [95% confidence interval (CI) = 0.90–2.23]), pre-eclampsia (1.70 [1.08–2.65]), and gestational diabetes (1.68 [1.25–2.25]). After removing women with pregnancy complications (n=30), the estimated aRR for the association between systolic blood pressure and preterm birth was 1.23 (95% CI= 0.99–1.54); for HDL-c and low birthweight, 0.97 (0.73–1.28); for diastolic blood pressure and small-for-gestational-age, 0.98 (0.81–1.20); and for systolic blood pressure and small-for-gestational-age, 1.18 (0.97–1.45).
Conclusions
High lipid levels before pregnancy predict an increased risk of pre-eclampsia and gestational diabetes. Reported associations between these pregnancy complications and later cardiovascular disease of the mother are probably explained, at least in part, by maternal conditions that precede pregnancy. Interventions to improve cardiovascular health before pregnancy may reduce risk of pregnancy complications.
doi:10.1097/EDE.0b013e318225c960
PMCID: PMC3157236  PMID: 21709559
24.  Novel Loci for Metabolic Networks and Multi-Tissue Expression Studies Reveal Genes for Atherosclerosis 
PLoS Genetics  2012;8(8):e1002907.
Association testing of multiple correlated phenotypes offers better power than univariate analysis of single traits. We analyzed 6,600 individuals from two population-based cohorts with both genome-wide SNP data and serum metabolomic profiles. From the observed correlation structure of 130 metabolites measured by nuclear magnetic resonance, we identified 11 metabolic networks and performed a multivariate genome-wide association analysis. We identified 34 genomic loci at genome-wide significance, of which 7 are novel. In comparison to univariate tests, multivariate association analysis identified nearly twice as many significant associations in total. Multi-tissue gene expression studies identified variants in our top loci, SERPINA1 and AQP9, as eQTLs and showed that SERPINA1 and AQP9 expression in human blood was associated with metabolites from their corresponding metabolic networks. Finally, liver expression of AQP9 was associated with atherosclerotic lesion area in mice, and in human arterial tissue both SERPINA1 and AQP9 were shown to be upregulated (6.3-fold and 4.6-fold, respectively) in atherosclerotic plaques. Our study illustrates the power of multi-phenotype GWAS and highlights candidate genes for atherosclerosis.
Author Summary
In this study, we aim to identify novel genetic variants for metabolism, characterize their effects on nearby genes, and show that the nearby genes are associated with metabolism and atherosclerosis. To discover new genetic variants, we use an alternative approach to traditional genome-wide association studies: we leverage the information in phenotype covariance to increase our statistical power. We identify variants at seven novel loci and then show that our top signals drive expression of nearby genes AQP9 and SERPINA1 in multiple tissues. We demonstrate that AQP9 and SERPINA1 gene expression, in turn, is associated with metabolite levels. Finally, we show that the genes are associated with atherosclerosis using mouse atherosclerotic lesion size (AQP9) as well as tissue from healthy human arteries and atherosclerotic plaques (AQP9 and SERPINA1). This study illustrates that multivariate analysis of correlated metabolites can boost power for gene discovery substantially. Further functional work will need to be performed to elucidate the biological role of SERPINA1 and AQP9 in atherosclerosis.
doi:10.1371/journal.pgen.1002907
PMCID: PMC3420921  PMID: 22916037
25.  Evidence of Inbreeding Depression on Human Height 
McQuillan, Ruth | Eklund, Niina | Pirastu, Nicola | Kuningas, Maris | McEvoy, Brian P. | Esko, Tõnu | Corre, Tanguy | Davies, Gail | Kaakinen, Marika | Lyytikäinen, Leo-Pekka | Kristiansson, Kati | Havulinna, Aki S. | Gögele, Martin | Vitart, Veronique | Tenesa, Albert | Aulchenko, Yurii | Hayward, Caroline | Johansson, Åsa | Boban, Mladen | Ulivi, Sheila | Robino, Antonietta | Boraska, Vesna | Igl, Wilmar | Wild, Sarah H. | Zgaga, Lina | Amin, Najaf | Theodoratou, Evropi | Polašek, Ozren | Girotto, Giorgia | Lopez, Lorna M. | Sala, Cinzia | Lahti, Jari | Laatikainen, Tiina | Prokopenko, Inga | Kals, Mart | Viikari, Jorma | Yang, Jian | Pouta, Anneli | Estrada, Karol | Hofman, Albert | Freimer, Nelson | Martin, Nicholas G. | Kähönen, Mika | Milani, Lili | Heliövaara, Markku | Vartiainen, Erkki | Räikkönen, Katri | Masciullo, Corrado | Starr, John M. | Hicks, Andrew A. | Esposito, Laura | Kolčić, Ivana | Farrington, Susan M. | Oostra, Ben | Zemunik, Tatijana | Campbell, Harry | Kirin, Mirna | Pehlic, Marina | Faletra, Flavio | Porteous, David | Pistis, Giorgio | Widén, Elisabeth | Salomaa, Veikko | Koskinen, Seppo | Fischer, Krista | Lehtimäki, Terho | Heath, Andrew | McCarthy, Mark I. | Rivadeneira, Fernando | Montgomery, Grant W. | Tiemeier, Henning | Hartikainen, Anna-Liisa | Madden, Pamela A. F. | d'Adamo, Pio | Hastie, Nicholas D. | Gyllensten, Ulf | Wright, Alan F. | van Duijn, Cornelia M. | Dunlop, Malcolm | Rudan, Igor | Gasparini, Paolo | Pramstaller, Peter P. | Deary, Ian J. | Toniolo, Daniela | Eriksson, Johan G. | Jula, Antti | Raitakari, Olli T. | Metspalu, Andres | Perola, Markus | Järvelin, Marjo-Riitta | Uitterlinden, André | Visscher, Peter M. | Wilson, James F. | Gibson, Greg
PLoS Genetics  2012;8(7):e1002655.
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.
Author Summary
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.
doi:10.1371/journal.pgen.1002655
PMCID: PMC3400549  PMID: 22829771

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