Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Evidence of inbreeding depression on human height.

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 (χ(2) = 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.

Genome-wide meta-analysis of common variant differences between men and women.

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.

Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.

BACKGROUND: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. METHODS: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. FINDINGS: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. INTERPRETATION: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. FUNDING: arcOGEN was funded by a special purpose grant from Arthritis Research UK.

Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits.

Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10(-5) . Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits.

Ethical aspects of human biobanks: a systematic review.

AIM: To systematically assess the existing literature on ethical aspects of human biobanks. METHOD: We searched the Web of Science and PubMed databases to find studies addressing ethical problems in biobanks with no limits set (study design, study population, time period, or language of publication). All identified articles published until November 2010 were included. We analyzed the type of published articles, journals publishing them, involvement of countries/institutions, year of publication, and citations received, and qualitatively assessed every article in order to identify ethical issues addressed by the majority of published research on human biobanking. RESULTS: Hundred and fifty four studies satisfied our review criteria. The studies mainly came from highly developed countries and were all published in the last two decades, with over half of them published in 2009 or 2010. They most commonly discussed the informed consent, privacy and identifiability, return of results to participants, importance of public trust, involvement of children, commercialization, the role of ethics boards, international data exchange, ownership of samples, and benefit sharing. CONCLUSIONS: The focus on ethical aspects is strongly present through the whole biobanking research field. Although there is a consensus on the old and most typical ethical issues, with further development of the field and increasingly complex structure of human biobanks, these issues will likely continue to arise and accumulate, hence requiring constant re-appraisal and continuing discussion.

Association of NOS3 tag polymorphisms with hypoxic-ischemic encephalopathy.

AIM: To test the association of NOS3 gene with hypoxic-ischemic encephalopathy (HIE). METHODS: The study included 110 unrelated term or preterm born children (69 boys and 41 girls) with HIE and 128 term and preterm born children (60 boys and 68 girls) without any neurological problems after the second year of life. Children with perinatal HIE fulfilled the diagnostic criteria for perinatal asphyxia. All children were admitted to the Clinical Hospital Split between 1992 and 2008. We analyzed 6 tagging single nucleotide polymorphisms (SNP) within NOS3 gene (rs3918186, rs3918188, rs1800783, rs1808593, rs3918227, rs1799983), in addition to previously confirmed NOS3-associated SNP rs1800779. Genotyping was conducted using real-time polymerase chain reaction (PCR). Association analyses were performed according to allelic and genotypic distribution. RESULTS: Allelic test did not show any SNP association with HIE. SNP rs1808593 showed genotype association (P=0.008) and rs1800783-rs1800779 TG haplotype showed an association with HIE (P<0.001). The study had 80% statistical power to detect (α=0.05) an effect with odds ratio (OR)=2.07 for rs3918186, OR=1.69 for rs3918188, OR=1.70 for rs1800783, OR=1.80 for rs1808593, OR=2.10 for rs3918227, OR=1.68 for rs1800779, and OR=1.76 for rs1799983, assuming an additive model. CONCLUSION: Despite the limited number of HIE patients, we observed genotypic and haplotype associations of NOS3 polymorphisms with HIE.

Large-scale association analysis of TNF/LTA gene region polymorphisms in type 2 diabetes.

BACKGROUND: The TNF/LTA locus has been a long-standing T2D candidate gene. Several studies have examined association of TNF/LTA SNPs with T2D but the majority have been small-scale and produced no convincing evidence of association. The purpose of this study is to examine T2D association of tag SNPs in the TNF/LTA region capturing the majority of common variation in a large-scale sample set of UK/Irish origin. METHODS: This study comprised a case-control (1520 cases and 2570 control samples) and a family-based component (423 parent-offspring trios). Eleven tag SNPs (rs928815, rs909253, rs746868, rs1041981 (T60N), rs1800750, rs1800629 (G-308A), rs361525 (G-238A), rs3093662, rs3093664, rs3093665, and rs3093668) were selected across the TNF/LTA locus and genotyped using a fluorescence-based competitive allele specific assay. Quality control of the obtained genotypes was performed prior to single- and multi-point association analyses under the additive model. RESULTS: We did not find any consistent SNP associations with T2D in the case-control or family-based datasets. CONCLUSIONS: The present study, designed to analyse a set of tag SNPs specifically selected to capture the majority of common variation in the TNF/LTA gene region, found no robust evidence for association with T2D. To investigate the presence of smaller effects of TNF/LTA gene variation with T2D, a large-scale meta-analysis will be required.

Historic, demographic, and genetic evidence for increased population frequencies of CCR5Delta32 mutation in Croatian Island isolates after lethal 15th century epidemics.

AIM: To assess the frequency of 32 base pair deletion in CCR5 (CCR5Delta32), which has been shown to confer resistance to HIV infection in a homozygous form, in 10 isolated island communities of Dalmatia, Croatia, with different histories of exposure to epidemics during and since the medieval period. METHODS: In 2002, DNA analysis of 100 randomly selected individuals from each of the 10 isolated communities of 5 Croatian islands (Susak, Rab, Vis, Lastovo, and Mljet) showed high levels of 3-generational endogamy, indicating limited gene flow. Five of the communities were decimated by epidemics of unknown cause between 1449-1456, while the other 5 villages remained unaffected. Genotyping of the CCR5 gene was performed using the polymerase chain reaction method with primers flanking the region containing 32-bp deletion. RESULTS: The frequency of CCR5Delta32 in the 5 villages affected by the epidemic was 6.1-10.0%, and 1.0-3.8% in the 5 unaffected villages. The Delta32 mutation was found in 71 of 916 alleles among the individuals from the affected villages (7.5%), and in 24 of 968 alleles in unaffected villages (2.5%, chi(2)=27.3, P<10-6). A previous study in 303 random Croatian blood donors showed the frequency of the CCR5 Delta32 of 7.1% in the general population. The difference remained significant after correcting for population structure using both STRAT and STRUCTURE software and the genomic control test, to ensure results do not arise from the background genetic differences. CONCLUSION: Our results and historical evidence, suggest that the mid-15th century epidemic could have acted as a selection pressure for the CCR5Delta32 mutation.

Genome-wide association study of biochemical traits in Korcula Island, Croatia.

AIM: To identify genetic variants underlying biochemical traits--total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, albumin, and fibrinogen, in a genome-wide association study in an isolated population where rare variants of larger effect may be more easily identified. METHODS: The study included 944 adult inhabitants of the island of Korcula, as a part of larger DNA-based genetic epidemiological study in 2007. Biochemical measurements were performed in a single laboratory with stringent internal and external quality control procedures. Examinees were genotyped using Human Hap370CNV chip by Illumina, with a genome-wide scan containing 346027 single nucleotide polymorphisms (SNP). RESULTS: A total of 31 SNPs were associated with 7 investigated traits at the level of P<1.00 x 10(-5). Nine of SNPs implicated the role of SLC2A9 in uric acid regulation (P=4.10 x 10(-6)-2.58 x 10(-12)), as previously found in other populations. All 22 remaining associations fell into the P=1.00 x 10(-5)-1.00 x 10(-6) significance range. One of them replicated the association between cholesteryl ester transfer protein (CETP) and HDL, and 7 associations were more than 100 kilobases away from the closest known gene. Nearby SNPs, rs4767631 and rs10444502, in gene kinase suppressor of ras 2 (KSR2) on chromosome 12 were associated with LDL cholesterol levels, and rs10444502 in the same gene with total cholesterol levels. Similarly, rs2839619 in gene PBX/knotted 1 homeobox 1 (PKNOX1) on chromosome 21 was associated with total and LDL cholesterol levels. The remaining 9 findings implied possible associations between phosphatidylethanolamine N-methyltransferase (PEMT) gene and total cholesterol; USP46, RAP1GDS1, and ZCCHC16 genes and triglycerides; BCAT1 and SLC14A2 genes and albumin; and NR3C2, GRIK2, and PCSK2 genes and fibrinogen. CONCLUSION: Although this study was underpowered for most of the reported associations to reach formal threshold of genome-wide significance under the assumption of independent multiple testing, replications of previous findings and consistency of association between the identified variants and more than one studied trait make such findings interesting for further functional follow-up studies. Changed allele frequencies in isolate population may contribute to identifying variants that would not be easily identified in much larger samples in outbred populations.

Retinopathy and nephropathy in type 1 diabetic patients--association with polymorphysms of vitamin D-receptor, TNF, Neuro-D and IL-1 receptor 1 genes.

Retinopathy and nephropathy are common late type 1 diabetes mellitus (T1D) complications. In this study we investigated whether individual differences in 4 candidate genes significantly contribute to development and progression of late complications in T1D patients. We examined 121 patients for the presence of diabetic retinopathy and nephropathy. We genotyped variants in vitamin D receptor (VDR) and tumor necrosis factor (TNF) genes in 47 patients and in NeuroD1 and interleukin-1 receptor 1 (IL1R1) genes in 35 patients. Diabetic retinopathy had 66 (55%) patients after a median of 13.0 years after diagnosis. Diabetic nephropathy had 14 (11.66%) patients, all of whom had already developed retinopathy. A significant correlation between the degree of diabetic retinopathy and mean microalbuminuria (MA) value has been found (chi2 = 54.18, p < 0.001). After correcting for duration of disease, only the VDR gene BsmI genotypes showed significant association with cumulative prevalence of diabetic retinopathy, while no investigated genetic polymorphysms could reliably predict diabetic nephropathy.

Association of TNF promoter polymorphisms with type 1 diabetes in the South Croatian population.

Type 1 diabetes mellitus (TIDM) is an autoimmune disease characterized by the destruction of pancreatic p cells. Tumor necrosis factor (TNF) is a pleotropic cytokine with potent immunomodulatory and inflammatory activity. Association studies of TNF polymorphisms and type 1 diabetes (TIDM) frequently demonstrated TNF involvement with TIDM. Although TNF may play an important role in the pathogenesis of TIDM, the genetic association of TNF región with the disease has not been conclusive because of the strong linkage disequilibrium with HLA genes. In this study, we examined two TNF promoter variants (rs 1800629 at position -308, and rs361525 at position -238) for TIDM association in 233 patients and 144 controls from the population of South Croatia. A higher frequency of TNF -308 A alíele and also, a more frequent specific -308A -238G haplotype in TIDM patients were observed with a limited significance. However, we did not find strong evidence of association of TNF promoter polymorphisms with TIDM. In order to elucidate the trae contribution of TNF to TIDM susceptibility in our population, more comprehensive studies with HLA adjustment in a larger sample are required.

NeuroD1 gene and interleukin-18 gene polymorphisms in type 1 diabetes in Dalmatian population of Southern Croatia.

AIM: To evaluate the frequency of known polymorphisms in the exon 2 of the NeuroD1 gene and in the interleukin (IL)-18 promoter region in patients with type 1 diabetes mellitus (T1DM) and in healthy control subjects in Dalmatia, Southern Croatia. METHODS: A total of 134 unrelated patients (73 men and 61 women) and 132 consecutive unrelated healthy controls (61 men and 71 women) from the Dalmatian region of southern Croatia were recruited for the study. NeuroD1 genotypes (GG, GA, AA) were identified by means of polymerase chain reaction followed by restriction fragment length polymorphism (PCR/RFLP). IL-18 polymorphism in the position -137 of the promoter region was detected by using PCR sequence-specific primers. RESULTS: Genotype distributions of both genes did not show significant difference between patients and controls. CONCLUSION: Our results suggest that NeuroD1 exon 2 and IL-18 promoter gene polymorphisms are not associated with development of T1DM susceptibility in the population of South Croatia. In addition to previously published positive correlations of these polymorphisms with development of T1DM among different world populations, our findings indicate the existence of ethnic variations in the association of these genes with disease development.

FokI polymorphism, vitamin D receptor, and interleukin-1 receptor haplotypes are associated with type 1 diabetes in the Dalmatian population.

Vitamin D and interleukin (IL)-1 have been suggested to function in the pathogenesis of type 1 diabetes mellitus (T1DM). Therefore, we examined the influence of gene polymorphisms in vitamin D receptor (VDR) and interleukin-1 receptor type I (IL-1-R1) on susceptibility to T1DM in the Dalmatian population of South Croatia. We genotyped 134 children with T1DM and 132 controls; for FokI polymorphism studies, we extended the control group to an additional 102 patients. The VDR gene polymorphism FokI displayed unequal distribution (P = 0.0049) between T1DM and control groups, with the ff genotype occurring more frequently in T1DM individuals whereas the VDR gene polymorphism Tru9I did not differ in frequency between studied groups. All tested polymorphisms of the IL-1-R1 gene [PstI, HinfI, and AluI (promoter region) and PstI-e (exon 1B region)] displayed no differences between cases and controls. Haplotype analysis of the VDR gene (FokI, BsmI, ApaI, TaqI, Tru9I) and of the IL-1-R1 gene (PstI, HinfI, AluI, PstI-e) found haplotypes VDR FbATu (P = 0.0388) and IL-1-R1 phap' (P = 0.0419) to be more frequent in T1DM patients whereas the BatU haplotype occurred more often in controls (P = 0.0064). Our findings indicate that the VDR FokI polymorphism and several VDR and IL-1-R1 haplotypes are associated with susceptibility to T1DM in the Dalmatian population.

Dietary Intake, FTO Genetic Variants, and Adiposity: A Combined Analysis of Over 16,000 Children and Adolescents.

The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1-18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10(-4)), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10(-4)): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10(-10)) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.

Using ancestry-informative markers to identify fine structure across 15 populations of European origin.

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia.

An evaluation of different meta-analysis approaches in the presence of allelic heterogeneity.

Meta-analysis has proven a useful tool in genetic association studies. Allelic heterogeneity can arise from ethnic background differences across populations being meta-analyzed (for example, in search of common frequency variants through genome-wide association studies), and through the presence of multiple low frequency and rare associated variants in the same functional unit of interest (for example, within a gene or a regulatory region). The latter challenge will be increasingly relevant in whole-genome and whole-exome sequencing studies investigating association with complex traits. Here, we evaluate the performance of different approaches to meta-analysis in the presence of allelic heterogeneity. We simulate allelic heterogeneity scenarios in three populations and examine the performance of current approaches to the analysis of these data. We show that current approaches can detect only a small fraction of common frequency causal variants. We also find that for low-frequency variants with large effects (odds ratios 2-3), single-point tests have high power, but also high false-positive rates. P-value based meta-analysis of summary results from allele-matching locus-wide tests outperforms collapsing approaches. We conclude that current strategies for the combination of genetic association data in the presence of allelic heterogeneity are insufficiently powered.

IL12RB2 gene is associated with the age of type 1 diabetes onset in Croatian family Trios.

BACKGROUND: Common complex diseases are influenced by both genetic and environmental factors. Many genetic factors overlap between various autoimmune diseases. The aim of the present study is to determine whether four genetic variants known to be risk variants for several autoimmune diseases could be associated with an increased susceptibility to type 1 diabetes mellitus. METHODS AND FINDINGS: We genotyped four genetic variants (rs2358817, rs1049550, rs6679356, rs9865818) within VTCN1, ANXA11, IL12RB2 and LPP genes respectively, in 265 T1DM family trios in Croatian population. We did not detect association of these polymorphisms with T1DM. However, quantitative transmission disequilibrium test (QTDT, orthogonal model) revealed a significant association between the age of onset of T1DM and IL12RB2 rs6679356 variant. An earlier onset of T1DM was associated with the rs6679356 minor dominant allele C (p = 0.005). The association remained significant even after the Bonferroni correction for multiple testing and permutation. CONCLUSIONS: Variants originally associated with juvenile idiopathic arthritis (VTCN1 gene), sarcoidosis (ANXA11 gene), primary biliary cirrhosis (IL12RB2 gene) and celiac disease (LPP gene) were not associated with type 1 diabetes in our dataset. Nevertheless, association of IL12RB2 rs6679356 polymorphism with the age of T1DM onset suggests that this gene plays a role in defining the time of disease onset.

Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

Glycosyltransferase B4GALNT1 and type 1 diabetes in Croatian population: clinical investigation.

OBJECTIVES: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by destruction of pancreatic beta cells. Gangliosides are thought to be a target of a variety of anti-islet autoantibodies. The formation of gangliosides is catalyzed by addition of sugar residues to complex glycoconjugate molecules by glycosyltransferases. Beta-1,4-N-acetyl-galactosaminyl transferase 1 is the enzyme involved in the synthesis of asialo, a, b and c-series gangliosides and it is coded by B4GALNT1 gene. DESIGN AND METHODS: We genotyped 2 B4GALNT1 tagSNPs, designed to capture 100% of common variation in the region, in 202 families and 199 controls from the Croatian population. RESULTS: Transmission disequilibrium test and case-control analysis did not detect an association of B4GALNT1 gene with T1DM. CONCLUSIONS: Expression of gangliosides requires coordinated work of many genes. There is enough evidence showing that gangliosides are plausible contributors to T1DM pathological processes and, therefore, future studies on different glycosyltransferase genes are necessary.