Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12

Romanos, Marcel; Freitag, Christine M.; Jacob, Christian; Craig, David W.; Dempfle, Astrid; Nguyen, Thuy Trang; Halperin, Rebecca F.; Walitza, Susanne; Renner, Tobias; Seitz, Christiane; Romanos, Jasmin; Pálmason, Haukur; Reif, Andreas; Heine, Monika; Windemuth-Kieselbach, Christine; Vogler, Christian; Sigmund, J; Warnke, Andreas; Schäfer, Helmut; Meyer, Jobst; Stephan, Dietrich A.; Lesch, Klaus‐Peter

doi:10.1038/mp.2008.12

Cited by 103 publications

(73 citation statements)

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“…The duplication of PDE4D6 is inherited from the affected mother and located on chromsome 5q11.2, a region adjacent to the 5q13.1 locus of genome-wide significance in a high-resolution linkage study to ADHD (B2.5 Mb 5 0 of rs895381, family P1). 5 It is noteworthy that the 5q12.1 deletion in patient 241 (also see preceding section) is only B250 kb upstream of a linkage interval flanked by markers D5S1968-D5S629 in an extended pedigree (Lin et al, unpublished results) and nominally significant association of several SNPs (highest ranking SNP rs17780175, P = 3.41 Â 10 À9 ) in PDE4D, was also revealed by a pooling-based genome-wide association (GWA) study in adult ADHD. 60 Of related interest, PDE4D variants that distinguish dependent versus non-dependent individuals abusing methamphetamine, alcohol, nicotine and other substances have been previously identified in several GWA studies of addiction vulnerability.…”

Section: Discussionmentioning

confidence: 99%

“…A linkage analysis of eight extended families with high density of ADHD using a B50 K single-nucleotide polymorphism (SNP) array-based genotyping assay by our group validated previously reported findings and also revealed several novel susceptibility loci. 5 One of these, the chromosome 16q locus, contributes to the genome-wide significant finding revealed by a meta-analysis comprising data from seven ADHD linkage scans. 6 However, the identified linkage regions for ADHD are generally large and not easily delimitable, even when the data are combined.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

et al. 2010

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Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domaincontaining protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 a subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a B3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P = 0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

et al. 2010

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“…Because of the strong dependence among the phenotypes and methods, a Bonferroni correction for multiple testing induces very conservative results and loss of power. 15 Therefore, we provide here only MOD scores and not P-values corrected for the multiple tests. As a reference, note, however, that MOD scores of 2.7 and 4.18 are required for a genome-wide suggestive and significant linkage, 16 respectively, using a conservative Bonferroni correction for each linkage analyses of a dimension with two subtypes (four linkage analyses per subtype).…”

Section: Discussionmentioning

confidence: 99%

Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder

et al. 2012

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This study introduces a novel way to use the lifetime ratings of symptoms of psychosis, mania and depression in genetic linkage analysis of schizophrenia (SZ) and bipolar disorder (BP). It suggests using a latent class model developed for family data to define more homogeneous symptom subtypes that are influenced by a smaller number of genes that will thus be more easily detectable. In a two-step approach, we proposed: (i) to form homogeneous clusters of subjects based on the symptom dimensions and (ii) to use the information from these homogeneous clusters in linkage analysis. This framework was applied to a unique SZ and BP sample composed of 1278 subjects from 48 large kindreds from the Eastern Quebec population. The results suggest that our strategy has the power to increase linkage signals previously obtained using the diagnosis as phenotype and allows for a better characterization of the linkage signals. This is the case for a linkage signal, which we formerly obtained in chromosome 13q and enhanced using the dimension mania. The analysis also suggests that the methods may detect new linkage signals not previously uncovered by using diagnosis alone, as in chromosomes 2q (delusion), 15q (bizarre behavior), 7p (anhedonia) and 9q (delusion). In the case of the 15q and 2q region, the results coincide with linkage signals detected in other studies. Our results support the view that dissecting phenotypic heterogeneity by modeling symptom dimensions may provide new insights into the genetics of SZ and BP.

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“…These include affected sib-pair (ASP) linkage studies 16 -24 and studies of extended multigenerational families. 25,26 These studies suggested linkage to 1p36, 2q21, 2q35, 4q13.2, 5p13, 5q13.1, 5q33.3, 6q12, 6q22 -23, 7p13, 7q21, 9q22, 11q22, 13q12, 14q12, 15q15, 16q23, 17p11, and several other regions with nominally significant evidence of linkage but no outstanding replications. The continued failure to replicate linkage findings for ADHD has led researchers to believe that genes affecting ADHD have common variants with very small effects that cannot be detected successfully with methods relying on linkage and hence advocated the use of association analysis.…”

Section: Introductionmentioning

confidence: 99%

Suggestive linkage of ADHD to chromosome 18q22 in a young genetically isolated Dutch population

et al. 2009

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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 41.5 for regions 6p22 (Heterogenetic log of odds (HLOD) ¼ 1.67) and 18q21-22 (HLOD ¼ 2.13) under a recessive model. We followed up these two regions in a larger sample of ADHD patients (n ¼ 21, 9 initial and 12 extra patients). The LOD scores did not increase after increasing the sample size (6p22 (HLOD ¼ 1.51), 18q21-22 (HLOD ¼ 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 ¼ 10 À5 ) and rs4149601 (P ¼ 10 À4 ) 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 41 in our genome-wide scan.

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Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12

Cited by 103 publications

References 35 publications

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder

Suggestive linkage of ADHD to chromosome 18q22 in a young genetically isolated Dutch population

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