The Experts below are selected from a list of 45966 Experts worldwide ranked by ideXlab platform
Lies Lahousse - One of the best experts on this subject based on the ideXlab platform.
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a genome wide linkage study for chronic obstructive pulmonary disease in a dutch Genetic Isolate identifies novel rare candidate variants
Frontiers in Genetics, 2018Co-Authors: Ivana Nedeljkovic, C C Van Diemen, Natalie Terzikhan, Judith M Vonk, Diana A Van Der Plaat, Lies Lahousse, Brian D HobbsAbstract:Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple Genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare Genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a Genetic Isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4-11q14.1 (LOD = 3.71) and 5q14.3-5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) < 0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.
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a genome wide linkage study for chronic obstructive pulmonary disease in a dutch Genetic Isolate identifies novel rare candidate variants
Frontiers in Genetics, 2018Co-Authors: Ivana Nedeljkovic, Natalie Terzikhan, Judith M Vonk, Lies Lahousse, Diana A Van Der Plaat, Cleo C Van Diemen, Brian D HobbsAbstract:Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple Genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare Genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a Genetic Isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 (log of odds (LOD) score=5.52), 11p15.4-11q14.1 (LOD=3.71) and 5q14.3-5q33.2 (LOD=3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.
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a genome wide linkage study for copd in a dutch Genetic Isolate
European Respiratory Journal, 2017Co-Authors: Ivana Nedeljkovic, C C Van Diemen, C M Van Duijn, Natalie Terzikhan, Judith M Vonk, Diana A Van Der Plaat, Lies Lahousse, Guy Brusselle, Marike H Boezen, Najaf AminAbstract:Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with common Genetic variants. Familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare Genetic variants underlying COPD through genome-wide linkage scan. Affected-only analysis was performed using 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a Genetic Isolate, Erasmus Rucphen Family (ERF) study. Potential causal variants were then selected in exome sequence data from the affected members of the families that contributed the most to the peak. The shared rare variants were further tested for association with COPD in the entire ERF study (N=657). Significant evidence for linkage was observed on chromosomes 15 (log of odds (LOD) score=5.52) and 11 (LOD=3.71). Chromosome 15 is a known COPD locus harbouring nicotinic receptors. In the chromosome 11 locus we identified several rare (minor allele frequency (MAF)<0.02) predicted pathogenic variants. They were shared among the affected family members and associated with COPD in the entire ERF study (P<0.03). The identified variants localize to genes including solute carrier family (SLC22A11), involved in the amino acids metabolism and ion transport; metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism; neuroblast differentiation-associated protein (AHNAK), reported by GWAS of blood biomarkers in COPD and Phospholipase C Beta 3 (PLCB3), reported by GWAS of asthma. In conclusion, we have identified novel rare variants in plausible genes related to COPD, which will be further explored by replication using exome sequencing in a large independent population-based cohort.
Natalie Terzikhan - One of the best experts on this subject based on the ideXlab platform.
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a genome wide linkage study for chronic obstructive pulmonary disease in a dutch Genetic Isolate identifies novel rare candidate variants
Frontiers in Genetics, 2018Co-Authors: Ivana Nedeljkovic, C C Van Diemen, Natalie Terzikhan, Judith M Vonk, Diana A Van Der Plaat, Lies Lahousse, Brian D HobbsAbstract:Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple Genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare Genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a Genetic Isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4-11q14.1 (LOD = 3.71) and 5q14.3-5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) < 0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.
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a genome wide linkage study for chronic obstructive pulmonary disease in a dutch Genetic Isolate identifies novel rare candidate variants
Frontiers in Genetics, 2018Co-Authors: Ivana Nedeljkovic, Natalie Terzikhan, Judith M Vonk, Lies Lahousse, Diana A Van Der Plaat, Cleo C Van Diemen, Brian D HobbsAbstract:Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple Genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare Genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a Genetic Isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 (log of odds (LOD) score=5.52), 11p15.4-11q14.1 (LOD=3.71) and 5q14.3-5q33.2 (LOD=3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.
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a genome wide linkage study for copd in a dutch Genetic Isolate
European Respiratory Journal, 2017Co-Authors: Ivana Nedeljkovic, C C Van Diemen, C M Van Duijn, Natalie Terzikhan, Judith M Vonk, Diana A Van Der Plaat, Lies Lahousse, Guy Brusselle, Marike H Boezen, Najaf AminAbstract:Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with common Genetic variants. Familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare Genetic variants underlying COPD through genome-wide linkage scan. Affected-only analysis was performed using 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a Genetic Isolate, Erasmus Rucphen Family (ERF) study. Potential causal variants were then selected in exome sequence data from the affected members of the families that contributed the most to the peak. The shared rare variants were further tested for association with COPD in the entire ERF study (N=657). Significant evidence for linkage was observed on chromosomes 15 (log of odds (LOD) score=5.52) and 11 (LOD=3.71). Chromosome 15 is a known COPD locus harbouring nicotinic receptors. In the chromosome 11 locus we identified several rare (minor allele frequency (MAF)<0.02) predicted pathogenic variants. They were shared among the affected family members and associated with COPD in the entire ERF study (P<0.03). The identified variants localize to genes including solute carrier family (SLC22A11), involved in the amino acids metabolism and ion transport; metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism; neuroblast differentiation-associated protein (AHNAK), reported by GWAS of blood biomarkers in COPD and Phospholipase C Beta 3 (PLCB3), reported by GWAS of asthma. In conclusion, we have identified novel rare variants in plausible genes related to COPD, which will be further explored by replication using exome sequencing in a large independent population-based cohort.
Adele Damico - One of the best experts on this subject based on the ideXlab platform.
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allelic and phenotypic heterogeneity in 49 italian patients with the muscle form of cpt ii deficiency
Clinical Genetics, 2012Co-Authors: Marina Fanin, A Anichini, Denise Cassandrini, Chiara Fiorillo, Sara Scapolan, Carlo Minetti, M Cassanello, M A Donati, Gabriele Siciliano, Adele DamicoAbstract:As genotype-phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine-palmitoyl-transferase-II (CPT-II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a Genetic Isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life-threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering Genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.
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allelic and phenotypic heterogeneity in 49 italian patients with the muscle form of cpt ii deficiency
Clinical Genetics, 2012Co-Authors: Marina Fanin, A Anichini, Denise Cassandrini, Chiara Fiorillo, Sara Scapolan, Carlo Minetti, M Cassanello, M A Donati, Gabriele Siciliano, Adele DamicoAbstract:Fanin M, Anichini A, Cassandrini D, Fiorillo C, Scapolan S, Minetti C, Cassanello M, Donati MA, Siciliano G, D’Amico A, Lilliu F, Bruno C, Angelini C. Allelic and phenotypic heterogeneity in 49 Italian patients with the muscle form of CPT-II deficiency. As genotype–phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine-palmitoyl-transferase-II (CPT-II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a Genetic Isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life-threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering Genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.
Mauricio Arcosburgos - One of the best experts on this subject based on the ideXlab platform.
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environmental influences that affect attention deficit hyperactivity disorder study of a Genetic Isolate
European Child & Adolescent Psychiatry, 2007Co-Authors: David Pineda, Francisco Lopera, I C Puerta, Clara P Arango, Luis G Palacio, Vilma Merchan, Astrid Yuleth Galvis, Monica Uribe Gomez, Daniel Camilo Aguirre, Mauricio ArcosburgosAbstract:Three independent complex segregation analyses found that the cause of Attention Deficit/Hyperactivity Disorder (ADHD) was the presence of major genes interacting with environmental influences. In order to identify potential environmental risk factors for ADHD in the Paisa community--a very well described, Genetically Isolated group--we randomly selected a sample of 486 children between 6 and 11 years of age. This group included 200 children with ADHD (149 males and 51 females) and 286 healthy controls (135 males and 151 females). The ADHD DSM-IV diagnosis was obtained using the DICA and BASC evaluation instruments, and the children's mothers or grandmothers filled out a questionnaire on each child's exposure to prenatal, neonatal, and early childhood risk factors. The data were analyzed using cross tabulation and stepwise logistic multiple-regression analyses. Cross tabulation associated ADHD with a variety of factors, including miscarriage symptoms, premature delivery symptoms, maternal respiratory viral infection, moderate to severe physical illness in the mother during gestation, prenatal cigarette and alcohol exposure, neonatal seizures, asphyxia or anoxia, severe neonatal illness, mild speech retardation, moderate brain injury, and febrile seizures (odds ratio >or= 2, P or= 2.0, P < 0.05). Future studies on the risk of developing ADHD must include these environmental factors as covariates.
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pedigree disequilibrium test pdt replicates association and linkage between drd4 and adhd in multigenerational and extended pedigrees from a Genetic Isolate
Molecular Psychiatry, 2004Co-Authors: David Pineda, Francisco Lopera, Juan David Palacio, Mauricio Arcosburgos, Francisco X Castellanos, D Konecki, Judith L Rapoport, Kate BergAbstract:Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a Genetic Isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 Genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to Genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.
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attention deficit hyperactivity disorder adhd feasibility of linkage analysis in a Genetic Isolate using extended and multigenerational pedigrees
Clinical Genetics, 2002Co-Authors: Mauricio Arcosburgos, David Pineda, Francisco Lopera, Juan David Palacio, Francisco X Castellanos, Kate Berg, M Garcia, G C Henao, Luis G Palacio, Joan E BaileywilsonAbstract:Segregation analyses converge in explaining the predisposition to attention-deficit/hyperactivity disorder (ADHD) as the consequence of a major gene and exclude purely environmental or cultural transmission. As a result of the ADHD phenotype restrictions, collection of extended families or design of linkage studies using families has been extremely difficult and thus currently linkage studies have been performed using only concordant or discordant sib-pairs rather than large families. On the other hand, intergenerational studies are represented by the transmission disequilibrium test (TDT) using trios. We collected pedigree data on ADHD from the Paisa community from Antioquia, Colombia, a Genetic Isolate. The goal of this study was to Genetically map a putative gene predisposing to ADHD in a set of 27 multigenerational Paisa families. Here we present the results of a power simulation using SIMLINK to detect linkage of ADHD. ADHD was assumed to be a dichotomous trait with incomplete penetrance and a phenocopy rate of 3% in males and 0.2% in females. We simulated cosegregation of the trait and a marker locus in our pedigrees. We assumed Hardy-Weinberg and linkage equilibrium, equally frequent marker alleles and evaluated power at several recombination fractions between the trait and marker loci. Also, the ADHD trait was assumed to be Genetically heterogeneous and different functions of age-dependent penetrance were simulated. We found exceptionally good power to detect linkage (expected LOD > 14 if theta is 0.1 or less), and that the presence of heterogeneity up to 50% does not affect substantially the projected LOD scores even for a theta recombination value of 0.05 (eLOD > 5.87). Having now obtained blood samples and confirmatory interviews in five families (representing 20% of the projected number of families), we performed a new analysis. The expected mean LOD in these five families reached values close to 10 and remained invariant when heterogeneity and different penetrance models were considered. We discuss the relative benefits of using extended and multigenerational families for Genetic mapping studies as opposed to using nuclear families, affected sib pairs or sporadic cases which require the collection of over 1000 analytical units to get the same power exhibited by the small number of pedigrees described here.
David Pineda - One of the best experts on this subject based on the ideXlab platform.
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linkage and association analysis of adhd endophenotypes in extended and multigenerational pedigrees from a Genetic Isolate
Molecular Psychiatry, 2016Co-Authors: Claudio A Mastronardi, David Pineda, Francisco Lopera, Juan David Palacio, E Pillai, Ariel F Martinez, Jorge I Velez, Hardip R Patel, Simon Easteal, Maria T AcostaAbstract:Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying Genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new Genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The Genetic information provided by this study offers a novel and complementary method of assessing the Genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.
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potential cognitive endophenotypes in multigenerational families segregating adhd from a Genetic Isolate
Adhd Attention Deficit and Hyperactivity Disorders, 2011Co-Authors: David Pineda, Francisco Lopera, I C Puerta, Natalia Trujilloorrego, Daniel Camilo Aguirreacevedo, Liliana Hincapiehenao, Clara P Arango, Maria T Acosta, Sandra I Holzinger, Juan David PalacioAbstract:Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the Genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a Genetic Isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between Genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high Genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association.
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Polymorphisms in the neural nicotinic acetylcholine receptor α4 subunit (CHRNA4) are associated with ADHD in a Genetic Isolate
ADHD Attention Deficit and Hyperactivity Disorders, 2009Co-Authors: Deeann Wallis, David Pineda, Francisco Lopera, Juan David Palacio, Mauricio Arcos-burgos, Mahim Jain, F. Xavier Castellanos, Horia Stanescu, Daniel Pineda, Kate BergAbstract:The neural nicotinic acetylcholine receptor α4 subunit (CHRNA4), at 20q13.2–q13.3, is an important candidate gene for conferring susceptibility to attention deficit/hyperactivity disorder (ADHD). Several studies have already looked for association/linkage between ADHD and CHRNA4 in different populations. We used the Pedigree Disequilibrium Test to search for evidence of association between ADHD and six SNP marker loci in families from the Isolated Paisa population. We found that the T allele of SNP rs6090384 exhibits a deficit of transmission in unaffected individuals (OR = 5.43, IC 1.54–19.13) (global P value = 0.014). We also found significant association and linkage to extended haplotypes rs2273502-rs6090384 (combination of variants C–T, respectively) ( P = 0.02) and rs6090384-rs6090387 ( P = 0.04) (combination of variants T–G, respectively). SNP rs6090384, variant T, has also been reported to be associated with inattention in a previous study. This makes ours the ninth study to examine the association of CHRNA4 with ADHD and the seventh one to find evidence for association in a population with a different ethnicity.
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environmental influences that affect attention deficit hyperactivity disorder study of a Genetic Isolate
European Child & Adolescent Psychiatry, 2007Co-Authors: David Pineda, Francisco Lopera, I C Puerta, Clara P Arango, Luis G Palacio, Vilma Merchan, Astrid Yuleth Galvis, Monica Uribe Gomez, Daniel Camilo Aguirre, Mauricio ArcosburgosAbstract:Three independent complex segregation analyses found that the cause of Attention Deficit/Hyperactivity Disorder (ADHD) was the presence of major genes interacting with environmental influences. In order to identify potential environmental risk factors for ADHD in the Paisa community--a very well described, Genetically Isolated group--we randomly selected a sample of 486 children between 6 and 11 years of age. This group included 200 children with ADHD (149 males and 51 females) and 286 healthy controls (135 males and 151 females). The ADHD DSM-IV diagnosis was obtained using the DICA and BASC evaluation instruments, and the children's mothers or grandmothers filled out a questionnaire on each child's exposure to prenatal, neonatal, and early childhood risk factors. The data were analyzed using cross tabulation and stepwise logistic multiple-regression analyses. Cross tabulation associated ADHD with a variety of factors, including miscarriage symptoms, premature delivery symptoms, maternal respiratory viral infection, moderate to severe physical illness in the mother during gestation, prenatal cigarette and alcohol exposure, neonatal seizures, asphyxia or anoxia, severe neonatal illness, mild speech retardation, moderate brain injury, and febrile seizures (odds ratio >or= 2, P or= 2.0, P < 0.05). Future studies on the risk of developing ADHD must include these environmental factors as covariates.
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pedigree disequilibrium test pdt replicates association and linkage between drd4 and adhd in multigenerational and extended pedigrees from a Genetic Isolate
Molecular Psychiatry, 2004Co-Authors: David Pineda, Francisco Lopera, Juan David Palacio, Mauricio Arcosburgos, Francisco X Castellanos, D Konecki, Judith L Rapoport, Kate BergAbstract:Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a Genetic Isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 Genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to Genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.