RESUMO
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by â¼9720 regulatory modules, of which â¼3000 operate in multiple tissues and â¼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
Assuntos
Doenças Inflamatórias Intestinais/genética , Herança Multifatorial , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doença de Crohn/genética , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Análise de Sequência de DNARESUMO
Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable, neuropsychiatric disorder among children. Linkage studies in isolated populations have proved powerful to detect variants for complex diseases, such as ADHD. We performed a genome-wide linkage scan for ADHD in nine patients from a genetically isolated population in the Netherlands, who were linked to each other within 10 generations through multiple lines of descent. The genome-wide scan was performed with a set of 400 microsatellite markers with an average spacing of +/-10-12 cM. We performed multipoint parametric linkage analyses using both recessive and dominant models. Our genome scan pointed to several chromosomal regions that may harbour ADHD susceptibility genes. None exceeded the empirical genome-wide significance threshold, but the Log of odds (LOD) scores were >1.5 for regions 6p22 (Heterogenetic log of odds (HLOD)=1.67) and 18q21-22 (HLOD=2.13) under a recessive model. We followed up these two regions in a larger sample of ADHD patients (n=21, 9 initial and 12 extra patients). The LOD scores did not increase after increasing the sample size (6p22 (HLOD=1.51), 18q21-22 (HLOD=1.83)). However, the LOD score on 6p22 increased to 2 when a separate analysis was performed for the inattentive type ADHD children. The linkage region on chromosome 18q overlaps with the findings of association of rs2311120 (P=10(-5)) and rs4149601 (P=10(-4)) in the genome-wide association analysis for ADHD performed by the Genetic Association Information Network consortium. Furthermore, there was an excess of regions harbouring serotonin receptors (HTR1B, HTR1E, HTR4, HTR1D, and HTR6) that showed a LOD score >1 in our genome-wide scan.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Cromossomos Humanos Par 18/genética , Ligação Genética , Adolescente , Criança , DNA/análise , DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Países Baixos , Linhagem , Receptores de Serotonina/genéticaRESUMO
Most studies on the genetic determinants of blood pressure and vascular complications of type 2 diabetes have focused on the effects of single genes. These studies often have yielded conflicting results. Therefore, we examined the combined effects of three renin-angiotensin system (RAS) genes and three salt sensitivity genes in relation to blood pressure and atherosclerosis in the total population and type 2 diabetic patients. The study was a part of the Rotterdam Study, a population-based cohort study. We have genotyped three RAS gene polymorphisms and three salt sensitivity gene polymorphisms. Diabetic patients with three risk genotypes of the RAS genes had a 6.9 mmHg higher systolic blood pressure (P for trend = 0.04) and a 6.0 mmHg higher pulse pressure (P for trend = 0.03) than those who did not carry any risk genotypes. Diabetic patients with three risk genotypes of the salt sensitivity genes had a 9.0 mmHg higher systolic blood pressure (P = 0.19) and a 13.1 mmHg higher pulse pressure (P = 0.02). Diabetic patients who carried three risk genotypes for the RAS genes had a higher mean intima-media thickness than those with two risk genotypes (mean difference 0.04 mm, P = 0.02). We found that among type 2 diabetic patients, mean systolic blood pressure, pulse pressure, and risk of hypertension increased with the number of risk genotypes for the RAS genes and the salt sensitivity genes.
