1,080 research outputs found
Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite
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Analysis of GWAS top hits in ADHD suggests association to two polymorphisms located in genes expressed in the cerebellum
No full textAttention deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder influenced by genetic factors. Several chromosomal regions with potential linkage and candidate genes associations have been reported, but findings are often inconsistent and non-replicated. The few genome-wide association studies (GWAS) carried out so far differ for study design and phenotypes analyzed, and did not detect any association significant at the genome-wide level. In the present study we examined the top SNPs reported in the GWAS by Neale et al. [2008] in an independent cohort. Although our sample size is smaller (415 trios vs. 909), the power was sufficient to confirm the role of candidate markers in ADHD if a true association exists. Two out of 36 top SNPs were significant at alpha = 0.05 in our sample, although none was still significant after correction for multiple tests. These two SNPs are both located in genes coding for as yet uncharacterized proteins expressed in the cerebellum, XKR4 in 8q12.1, and FAM190A in 4q22.1. Three other FAM190A SNPs have TDT P-values of <10(-5) in our sample, a level of significance only reached by a total of five SNPs in our genome-wide data. While these findings could be due to chance, we cannot exclude that these markers are indeed associated to disease risk. Remarkably, brain imaging studies have shown reduction of the posterior inferior cerebellar lobules volume of ADHD boys and girls compared to controls, persistent with age and not present in unaffected siblings, suggesting that the cerebellum may be directly related to pathophysiology of ADHD. (C) 2010 Wiley-Liss, Inc
Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1A.
No full textOBJECTIVES:
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common developmental disorder. Although a few confirmed associations have emerged from candidate gene studies, these have shown the same limitations that have become evident in the study of other complex diseases, often with inconsistent and nonreplicated results across different studies.
METHODS:
In this report, 27 ADHD candidate genes were explored in greater depth using high-density tag single nucleotide polymorphism (SNP) genotyping. Association with 557 SNPs was tested using the transmission disequilibrium test in 270 nuclear pedigrees selected from an ongoing ADHD genetic study that includes all disease subtypes.
RESULTS:
SNPs in seven genes including SLC1A3, SLC6A3, HTR4, ADRA1A, HTR2A, SNAP25, and COMT showed a nominal level of association with ADHD (P values <0.05), but none remained significant after a stringent correction for the total number of tests performed.
CONCLUSION:
The strongest signal emerged from SNPs in the promoter region (rs3808585) and in an intron (rs17426222, rs4732682, rs573514) of ADRA1A, all located within the same haplotype block. Some of the SNPs in HTR2A and COMT have already been reported by others, whereas other SNPs will need confirmation in independent samples
Replication of Neuroblastoma SNP Association at the BARD1 Locus in African-Americans
No full textBackground: Neuroblastoma is an often fatal pediatric cancer more frequent in European-American than African-American children. African-American children, however, are at higher risk for the more severe form of neuroblastoma and have worse overall survival than European-American children. Genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNP) associated to neuroblastoma in children of European descent. Knowledge of their association to neuroblastoma in African-American children is still lacking. Methods: We genotyped and imputed SNPs located in three gene regions reported to be associated to neuroblastoma in children of European descent, and tested them for association in 390 African-American patients with neuroblastoma compared with 2,500 healthy, ethnically matched controls. Results: SNPs in the BARD1 gene region show a similar pattern of association to neuroblastoma in African-American and European-American children. The more restricted extent of linkage disequilibrium in the African-American population suggests a smaller candidate region for the putative causal variants than previously reported. Limited association was observed at the other two gene regions tested, including LMO1 in 11p15 and FLJ22536 in 6p22. Conclusions: Common BARD1 SNPs affect risk of neuroblastoma in African-Americans. The role of other SNPs associated to neuroblastoma in children of European descent could not be confirmed, possibly due to different patterns of linkage disequilibrium or limited statistical power to detect association to variants with small effect on disease risk. Extension of GWAS to populations of African descent is important to confirm their results and validity beyond the European populations and can help to refine the location of the putative causal variants. Cancer Epidemiol Biomarkers Prev; 21(4); 658-63. (C) 2012 AACR
Genome-Wide Linkage Analysis to Identify Genetic Modifiers of ALK Mutation Penetrance in Familial Neuroblastoma.
No full textBackground: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB. Methods: To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations. Results: The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance. Conclusions: This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases
Genetic Analysis in African American Children Supports Ancestry-Specific Neuroblastoma Susceptibility
No full textBackground: Neuroblastoma is rarer in African American (AA) children compared with American children of European descent. AA children affected with neuroblastoma, however, more frequently develop the high-risk form of the disease. Methods: We have genotyped an AA cohort of 629 neuroblastoma cases (254 high-risk) and 2,990 controls to investigate genetic susceptibility to neuroblastoma in AAs. Results: We confirmed the known neuroblastoma susceptibility gene BARD1 at genome-wide significance in the subset of high-risk cases. We also estimated local admixture across the autosomal genome in the AA cases and controls and detected a signal at 4q31.22 where cases show an increase in European ancestry. A region at 17p13.1 showed increased African ancestry in the subgroup of high-risk cases with respect to intermediateand low-risk cases. Using results from our published European American (EA) genome-wide association study (GWAS), we found that a polygenic score that included all independent SNPs showed a highly significant association (P value = 1.8 × 10-73) and explained 19% of disease risk variance in an independent EA cohort. In contrast, the best fit polygenic score (P value = 3.2 × 10-11) in AAs included only 22 independent SNPs with association P value < 2.75 ×10_6 in the EA GWAS, and explained 2% of neuroblastoma risk variance. The significance of the polygenic score dropped rapidly with inclusion of additional SNPs. Conclusions: These findings suggest that several common variants contribute to risk of neuroblastoma in an ancestry-specific fashion
Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: Suggestive association signals in ADRA1A
No full textObjectives Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common developmental disorder. Although a few confirmed associations have emerged from candidate gene studies, these have shown the same limitations that have become evident in the study of other complex diseases, often with inconsistent and nonreplicated results across different studies. Methods In this report, 27 ADHD candidate genes were explored in greater depth using high-density tag single nucleotide polymorphism (SNP) genotyping. Association with 557 SNPs was tested using the transmission disequilibrium test in 270 nuclear pedigrees selected from an ongoing ADHD genetic study that includes all disease subtypes. Results SNPs in seven genes including SLC1A3, SLC6A3, HTR4, ADRA1A, HTR2A, SNAP25, and COMT showed a nominal level of association with ADHD (P values 0.05), but none remained significant after a stringent correction for the total number of tests performed. Conclusion The strongest signal emerged from SNPs in the promoter region (rs3808585) and in an intron (rs17426222, rs4732682, rs573514) of ADRA1A, all located within the same haplotype block. Some of the SNPs inHTR2A and COMT have already been reported by others, whereas other SNPs will need confirmation in independent samples. © 2009 Wolters Kluwer Health | Lippincott Williams &Wilkins
Hundreds of variants clustered in genomic loci and biological pathways affect human height
No full textMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways
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