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Despite a wealth of evidence for the role of genetics in attention deficit hyperactivity disorder (ADHD), specific and definitive genetic mechanisms have not been identified. Pathway analyses, a subset of gene‐set analyses, extend the knowledge gained from genome‐wide association studies (GWAS) by providing functional context for genetic associations. However, there are numerous methods for association testing of gene sets and no real consensus regarding the best approach. The present study applied six pathway analysis methods to identify pathways associated with ADHD in two GWAS datasets from the Psychiatric Genomics Consortium. Methods that utilize genotypes to model pathway‐level effects identified more replicable pathway associations than methods using summary statistics. In addition, pathways implicated by more than one method were significantly more likely to replicate. A number of brain‐relevant pathways, such as RhoA signaling, glycosaminoglycan biosynthesis, fibroblast growth factor receptor activity, and pathways containing potassium channel genes, were nominally significant by multiple methods in both datasets. These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross‐method convergence in evaluating pathway analysis results. © 2016 Wiley Periodicals, Inc.

Acetylcholine influences the speed of information processing. We examined the effect of the rs3841324 polymorphism (LS) and the rs16969968 (GA) polymorphism on response speed in the Stroop task and the Negative priming task. These polymorphisms are located in the gene that encodes the nicotinic acetylcholine receptor 5-subunit (CHRNA5). Male carriers of the rs3841324 SS genotype and the rs16969968 GG genotype were faster than male carriers of at least one L allele or one A allele. In contrast, female carriers of the rs3841324 SS genotype and the rs16969968 GG genotype were slower than female carriers of at least one L allele or one A allele. These results indicate that the minor alleles of both polymorphisms modulate response speed in a sex-dependent, diametrically opposed manner.

Hyperactivity of the hypothalamus–pituitary–adrenal HPA axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene GR, NR3C1. GRpolymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GRSNP rs10482605, located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GRSNPs to further characterize GRhaplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a AG SNP in exon 9beta rs6198, associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GRSNPs in linkage disequilibrium are responsible for both regulation of GRexpression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression. © 2008 WileyLiss, Inc.

Genetic contribution to the development of attention deficit hyperactivity disorder ADHD is well established. Seven independent genomewide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis GSMA to identify the genomic region with most consistent linkage evidence across the studies. Genomewide significant linkage PSR  0.00034, POR  0.04 was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes. © 2008 WileyLiss, Inc.

Zusammenfassung.Theoretischer Hintergrund:Autistische Störungen zeichnen sich durch Einschränkungen in den Bereichen Soziale Interaktion, Kommunikation und stereotypes, restriktives Verhalten aus. Bisher existiert noch kein deutschsprachiges Selbstbeurteilungsinstrument, das zum Screening bei Verdacht auf autistische Störung eingesetzt werden kann. Fragestellung:Testtheoretische Analyse des Screening-Fragebogens Autismus-Spektrum-Quotient (AQ). Methode:Die psychometrischen Kennwerte des AQ wurden in zwei nicht-klinischen, einer klinisch-forensischen und einer Stichprobe mit High-functioning Autismus/Asperger Syndrom ermittelt. Ergebnisse:Auf Grund einer teilweise sehr niedriger Trennschärfe der Einzelitems wurde eine Kurzversion des Fragebogens (AQ-k) gebildet, bestehend aus Items mit ausreichender Trennschärfe. Die Hauptkomponentenanalyse des AQ-k resultierte in drei Faktoren (Soziale Interaktion und Spontaneität, Fantasie und Vorstellungsvermögen, Kommunikation und Reziprozität), deren innere Konsistenzen zwischen 0,65-0,87 lagen. Die Retest-Reliabilität war zufrieden stellend, ebenso die externe Validität. Die Sensitivitätsanalyse ergab einen cut-off-Wert von 17. Schlussfolgerung:Der AQ-k eignet sich als Selbstbeurteilungsinstrument zum Screening auf autistische Störung bei normal begabten Personen ab 16 Jahren. Eine Diagnose kann durch das Instrument nicht gestellt werden.

The cadherin gene CELSR1is specifically expressed in the brain and located on chromosome 22q13.33, a region that has recently been shown to be involved in the etiopathogenesis of familial catatonic schizophrenia. The gene is a strong positional candidate and was considered for mutational analysis. A total of 17 allelic variants of CELSR1was found by sequencing all 35 exons, intron–exon junctions, and the putative promoter region by screening two patients from a large family mainly supporting this locus, and three control subjects in a first step. No variant exclusively co-segregates with the disease in the large pedigree, providing evidence that CELSR1is not causative for the pathogenesis of catatonic schizophrenia in this family.

Functional characterization studies revealed that transcriptional activity of the human monoamine oxidase A (MAOA) gene is modulated by a polymorphic repetitive sequence located approximately 1.2 kb upstream of the ATG codon. To investigate the possible influence of the allelic variants of the MAOA gene-linked polymorphic region (MAOA-LPR) on the genetic predisposition to psychiatric disorders, we have performed a case-control association study. 174 patients with affective disorders and 258 patients with schizophrenia according to DSM-IV, as well as 229 population controls were tested. Statistical analysis showed no significant differences in allele or genotype frequencies between control and patient groups. Our results suggest that there is no association between MAOA-LPR genotype and susceptibility to recurrent major depression, bipolar disorder, and schizophrenia in our population. © 2001 Wiley-Liss, Inc.

The human synapsin III gene (synapsin III) is a member of a neuron-specific phosphoprotein gene family involved in short-term neurotransmitter release. We mapped synapsin III to chromosomal region 22q13 (13.1–13.31) by fluorescence in situ hybridization, a region that has been identified as a potential schizophrenia susceptibility locus. The dinucleotide repeat marker D22S280 located in intron 5 of synapsin III was genotyped in a linkage and family-based association study to assess the role of the synapsin III locus in the etiology of schizophrenia. In 12 pedigrees with periodic catatonia comprising 135 individuals, we found exclusion of linkage of marker D22S280 using lod score analysis with autosomal dominant/recessive models as well as affected only LOD score methods with dominant/recessive models. In a family-based association study of 61 unrelated parent–offspring trios with schizophrenia (according to the the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM–IV, American Psychiatric Association, 1994]), we found no association of individual D22S280 alleles to disease. Results of a multiallelic transmission/disequilibrium test (TDTmax = 3.00; P = 0.55) challenged the possibility that D22S280 alleles appear with DSM–IV schizophrenia more frequently than expected. In addition, no evidence for gender differences or parent-of-origin effects were found. Thus, the synapsin III locus at chromosome 22q13 is not likely to contain a schizophrenia susceptibility gene. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:392–397, 2000. © 2000 Wiley-Liss, Inc.

IN a family-based association study we investigated transmission of a multiallelic CAG repeat in a novel neuronal potassium channel gene, hSKCa3, in 59 parent/ offspring trios. In contrast to recent reports of an association of moderately large repeats with schizophrenia in case-control studies, our findings indicate that short CAG repeats (≤ 19 repeats) are transmitted at an increased frequency to schizophrenic offspring (p= 0.014), particularly among familial cases (p= 0.007). No evidence for a parent-of-origin effect was found. Multiallelic TDT procedure showed no association of individual CAG repeats to schizophrenia. Further studies using family-based designs should clarify whether hSKCa3is a susceptibility factor to schizophrenia or co-segregates with a major disease gene in tight linkage.

Campomelic dysplasia (CMPD1) and autosomal XY sex reversal (SRA1) are caused by mutations in the SRY-related gene SOX9 on 17q. Unexpectedly, the 17q breakpoints in four CMPD l translocation cases previously analyzed by us and others map 50 kb or more from SOX9. Here, we present clinical, cytogenetic, and molecular data from a new CMPD1/SRA1 patient with t(6; 17) (q14; q24). Fluorescence in situ hybridization has shown that the 17q breakpoint in this case maps to the same region as the breakpoints in the other translocation cases, at least 130 kb from SOX9. Likewise, the breakpoints in two of the previously described cases also map more than 130 kb and, as shown by pulsed field gel electrophoresis analysis, at most 400 kb or 690 kb from SOX9. By using a SOX9 coding sequence polymorphism, expression of both SOX9 alleles has been demonstrated by the reverse transcriptase polymerase chain reaction in lymphoblastoid cells from one of the translocation cases.

Recessive mutations of the potassium chloride co-transporter 3 gene (SLC12A6, KCC3) cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN). SLC12A6 is localized on chromosome 15q14, a region where linkage to schizophrenia and bipolar disorder has previously been shown. Mutation analysis of SLC12A6 was carried out by direct sequencing of PCR-generated DNA fragments in two affected members of a multiplex family, and three non-affected individuals. A case-control study was performed to assess association of variants with bipolar disorder and schizophrenia in a large sample. Several variants including two rare single nucleotide polymorphisms (G/A, G/A) in the promoter and 5'-UTR, and a thymidine insertion in intron 4 were found. The two G variants and the insertion variant were co-inherited with chromosome 15-related schizophrenia in a large family that strongly supports the region on chromosome 15q14-15 between markers D15S144 and D15S132. Furthermore, they are in linkage disequilibrium with each other, and significantly associated with bipolar disorder in a case-control study. Our data strongly suggest that rare variants of SLC12A6 may represent risk factors for bipolar disorder.

Candidate genes for association studies in panic disorder are often selected on the basis of molecular mechanisms of drugs utilized in challenge tests such as m-chlorophenylpiperazine (mCPP), a non-selective 5-HT2C receptor agonist. Two novel, adjacent polymorphisms [(GT)12–18 and (CT)4–5] in the 5&Ymacr;-reory region of the X-chromosomal 5-HT2C receptor gene have recently been reported. We determined the allele frequency of long vs. short polymorphism haplotypes in a German and an Italian sample (combined n = 211) of panic disorder patients (DSM-III-R) and compared it with allele frequencies in two ethnically matched control samples (combined n = 226). In the German sample, a comparison of female genotypes containing the short haplotype vs. female genotypes containing only long haplotypes showed a significant difference (p = 0.01, ϰ2 analysis). In the Italian sample, however, this observation could not be replicated (p = 0.54, ϰ2 analysis). This argues against a major role for these promoter-associated 5-HT2C receptor gene length polymorphisms in the aetiopathogenesis of panic disorder.