TY  - JOUR
AB  - Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large-scale genome-wide association studies (GWAS). Methods for direct imputation of GWAS summary-statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage-disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500-subject coming from the 1000 Genome-Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic-mixture based solely on Z-scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary-statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post-traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS-studies.
AU  - Chatzinakos, C.*
AU  - Lee, D.*
AU  - Cai, N.
AU  - Vladimirov, V.I.*
AU  - Webb, B.T.*
AU  - Riley, B.P.*
AU  - Flint, J.*
AU  - Kendler, K.S.*
AU  - Ressler, K.J.*
AU  - Daskalakis, N.P.*
AU  - Bacanu, S.A.*
C1  - 61306
C2  - 50121
SP  - 16-27
TI  - Increasing the resolution and precision of psychiatric genome-wide association studies by re-imputing summary statistics using a large, diverse reference panel.
JO  - Am. J. Med. Genet. B
VL  - 196
IS  - 1
PY  - 2021
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Genetic signal detection in genome-wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2-P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as-is to ethnically mixed-cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example,MAGMA, we applied JEPEGMIX2-P to summary statistics of most large meta-analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.
AU  - Chatzinakos, C.*
AU  - Georgiadis, F.*
AU  - Lee, D.*
AU  - Cai, N.
AU  - Vladimirov, V.I.*
AU  - Docherty, A.*
AU  - Webb, B.T.*
AU  - Riley, B.P.*
AU  - Flint, J.*
AU  - Kendler, K.S.*
AU  - Daskalakis, N.P.*
AU  - Bacanu, S.A.*
C1  - 60140
C2  - 49271
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 454-463
TI  - TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders.
JO  - Am. J. Med. Genet. B
VL  - 183
IS  - 8
PB  - Wiley
PY  - 2020
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents. No mutations in known HSAN genes were identified. However, filtering for genes carrying two rare sequence variations detected 13 homozygous single nucleotide variants (SNV), all being located on chromosome 1. Further analysis strongly suggested that this finding might be best explained by uniparental disomy of chromosome 1. Because NTRK1 is also located on chromosome 1, we re-evaluated WES data and detected a novel intronic sequence variation at position c.2188-12 C>A, homozygously because of uniparental disomy. Subsequent analysis of NTRK1 transcripts in peripheral blood cells of the patient revealed an influence of the variant on mRNA splicing. The C>A transversion generated a novel splice-site, which led to the incorporation of 10 intronic bases into the NTRK1 mRNA and consequently to a non-functional gene product.
AU  - Kurth, I.*
AU  - Baumgartner, M.*
AU  - Schabhüttl, M.*
AU  - Tomni, C.*
AU  - Windhager, R.*
AU  - Strom, T.M.
AU  - Wieland, T.
AU  - Gremel, K.*
AU  - Auer-Grumbach, M.*
C1  - 48616
C2  - 41221
CY  - Hoboken
SP  - 875-878
TI  - Whole exome sequencing in congenital pain insensitivity identifies a novel causative intronic NTRK1-mutation due to uniparental disomy.
JO  - Am. J. Med. Genet. B
VL  - 171
IS  - 6
PB  - Wiley-blackwell
PY  - 2016
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - 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.
AU  - Mooney, M.A.*
AU  - McWeeney, S.K.*
AU  - Faraone, S.V.*
AU  - Hinney, A.*
AU  - Hebebrand, J.*
AU  - IMAGE2 Consortium*
AU  - German ADHD GWAS Group*
AU  - Nigg, J.T.*
AU  - Wilmot, B.*
AU  - EUMODIC Consortium (Wichmann, H.-E.)
C1  - 49554
C2  - 30493
SP  - 815-826
TI  - Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach.
JO  - Am. J. Med. Genet. B
VL  - 171
IS  - 6
PY  - 2016
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning.
AU  - Pappa, I.*
AU  - St Pourcain, B.*
AU  - Benke, K.*
AU  - Cavadino, A.*
AU  - Hakulinen, C.*
AU  - Nivard, M.G.*
AU  - Nolte, I.M.*
AU  - Tiesler, C.M.
AU  - Bakermans-Kranenburg, M.J.*
AU  - Davies, G.E.*
AU  - Evans, D.M*
AU  - Geoffroy, M.C.*
AU  - Grallert, H.
AU  - Groen-Blokhuis, M.M.*
AU  - Hudziak, J.J.*
AU  - Kemp, J.P.*
AU  - Keltikangas-Järvinen, L.*
AU  - McMahon, G.*
AU  - Mileva-Seitz, V.R.*
AU  - Motazedi, E.*
AU  - Power, C.*
AU  - Raitakari, O.T.*
AU  - Ring, S.M.*
AU  - Rivadeneira, F.*
AU  - Rodriguez, A.*
AU  - Scheet, P.A.*
AU  - Seppälä, I.*
AU  - Snieder, H.*
AU  - Standl, M.
AU  - Thiering, E.
AU  - Timpson, N.J.*
AU  - Veenstra, R.*
AU  - Velders, F.P.*
AU  - Whitehouse, A.J.*
AU  - Smith, G.D.*
AU  - Heinrich, J.
AU  - Hyppönen, E.*
AU  - Lehtimäki, T.*
AU  - Middeldorp, C.M.*
AU  - Oldehinkel, A.J.*
AU  - Pennell, C.E.*
AU  - Boomsma, D.I.*
AU  - Tiemeier, H.*
C1  - 45347
C2  - 37307
CY  - Hoboken
SP  - 562-572
TI  - A genome-wide approach to children's aggressive behavior: The EAGLE consortium.
JO  - Am. J. Med. Genet. B
VL  - 171
IS  - 5
PB  - Wiley-blackwell
PY  - 2016
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Deviations from normal body weight are observed prior to and after the onset of Alzheimer's disease (AD). Midlife obesity confers increased AD risk in later life, whereas late-life obesity is associated with decreased AD risk. The role of underweight and weight loss for AD risk is controversial. Based on the hypothesis of shared genetic variants for both obesity and AD, we analyzed the variants identified for AD or obesity from genome-wide association meta-analyses of the GERAD (AD, cases = 6,688, controls = 13,685) and GIANT (body mass index [BMI] as measure of obesity, n = 123,865) consortia. Our cross-disorder analysis of genome-wide significant 39 obesity SNPs and 23 AD SNPs in these two large data sets revealed that: (1) The AD SNP rs10838725 (p(AD) = 1.1 x 10(-08)) at the locus CELF1 is also genome-wide significant for obesity (pBMI = 7.35 x 10(-09)). (2) Four additional AD risk SNPs were nominally associated with obesity (rs17125944 at FERMT2, p(BMI) = 4.03 x 10(-05), p(BMI corr) = 2.50 x 10(-03); rs3851179 at PICALM; p(BMI) = 0.002, rs2075650 at TOMM40/APOE, p(BMI) = 0.024, rs3865444 at CD33, p(BMI) = 0.024). (3) SNPs at two of the obesity risk loci (rs4836133 downstream of ZNF608; p(AD) = 0.002 and at rs713586 downstream of RBJ/DNAJC27; p(AD) = 0.018) were nominally associated with AD risk. Additionally, among the SNPs used for confirmation in both studies the AD risk allele of rs1858973, with an AD association just below genome-wide significance (p(AD) = 7.20 x 10(-07)), was also associated with obesity (SNP at IQCK/GPRC5B; p(BMI) = 5.21 x 10(-06); p(corr) = 3.24 x 10(-04)). Our first GWAS based cross-disorder analysis for AD and obesity suggests that rs10838725 at the locus CELF1 might be relevant for both disorders.
AU  - Hinney, A.*
AU  - Albayrak, Ö.*
AU  - Antel, J.*
AU  - Volckmar, A.L.*
AU  - Sims, R.*
AU  - Chapman, J.*
AU  - Harold, D.*
AU  - Gerrish, A.*
AU  - Heid, I.M.*
AU  - Winkler, T.W.*
AU  - Scherag, A.*
AU  - Wiltfang, J.*
AU  - Williams, J.*
AU  - Hebebrand, J.*
AU  - GERAD Consortium (*)
AU  - IGAP Consortium (*)
AU  - GIANT Consortium (Albrecht, E.
AU  - Gieger, C.
AU  - Grallert, H.
AU  - Heid, I.M.
AU  - Illig, T.
AU  - Müller-Nurasyid, M.
AU  - Peters, A.
AU  - Thorand, B.
AU  - Wichmann, H.-E.)
C1  - 31790
C2  - 34839
CY  - Hoboken
SP  - 283-293
TI  - Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer's disease and obesity.
JO  - Am. J. Med. Genet. B
VL  - 165
IS  - 4
PB  - Wiley-Blackwell
PY  - 2014
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P=3.4x104; Pcorr=0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P=7.2x104; Pcorr=0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.
AU  - Albayrak, Ö.*
AU  - Pütter, C.*
AU  - Volckmar, A.L.*
AU  - Cichon, S.*
AU  - Hoffmann, P.*
AU  - Nöthen, M.M.*
AU  - Jöckel, K.-H.*
AU  - Schreiber, S.*
AU  - Wichmann, H.-E.
AU  - Faraone, S.V.*
AU  - Neale, B.M.*
AU  - Herpertz-Dahlmann, B.*
AU  - Lehmkuhl, G.*
AU  - Sinzig, J.*
AU  - Renner, T.J.*
AU  - Romanos, M.*
AU  - Warnke, A.*
AU  - Lesch, K.P.*
AU  - Reif, A.*
AU  - Schimmelmann, B.G.*
AU  - Scherag, A.*
AU  - Hebebrand, J.*
AU  - Hinney, A.*
AU  - Psychiatric GWAS Consortium ADHD Subgroup (*)
C1  - 25148
C2  - 31835
SP  - 295-305
TI  - Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder.
JO  - Am. J. Med. Genet. B
VL  - 162
IS  - 4
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Several aspects of sleep behavior such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of six sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317, 370, and 610K arrays and the SNPs in common between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the third intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (P = 1.3 × 10⁻⁶). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (P = 0.73). We have identified several other suggestive associations that await replication in an independent sample. We did not replicate the results from previous genome-wide analyses of self-reported sleep phenotypes after correction for multiple testing.
AU  - Byrne, E.M.*
AU  - Gehrman, P.R.*
AU  - Medland, S.E.*
AU  - Nyholt, D.R.*
AU  - Heath, A.C.*
AU  - Madden, P.A.*
AU  - Hickie, I.B.*
AU  - van Duijn, C.M.*
AU  - Henders, A.K.*
AU  - Montgomery, G.W.*
AU  - Martin, N.G.*
AU  - Wray, N.R.*
AU  - Chronogen Consortium (Meitinger, T.
AU  - Wichmann, H.-E.)
C1  - 30727
C2  - 33798
SP  - 439-451
TI  - A genome-wide association study of sleep habits and insomnia.
JO  - Am. J. Med. Genet. B
VL  - 162B
IS  - 5
PY  - 2013
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.
AU  - Hinney, A.*
AU  - Scherag, A.*
AU  - Jarick, I.*
AU  - Albayrak, Ö.*
AU  - Pütter, C.*
AU  - Pechlivanis, S.*
AU  - Dauvermann, M.R.*
AU  - Beck, S.*
AU  - Weber, H.*
AU  - Scherag, S.*
AU  - Nguyen, T.T.*
AU  - Volckmar, A.L.*
AU  - Knoll, N.*
AU  - Faraone, S.V.*
AU  - Neale, B.M.*
AU  - Franke, B.*
AU  - Cichon, S.*
AU  - Hoffmann, P.*
AU  - Nöthen, M.M.*
AU  - Schreiber, S.*
AU  - Jöckel, K.-H.*
AU  - Wichmann, H.-E.
AU  - Freitag, C.*
AU  - Lempp, T.*
AU  - Meyer, J.*
AU  - Gilsbach, S.*
AU  - Herpertz-Dahlmann, B.*
AU  - Sinzig, J.*
AU  - Lehmkuhl, G.*
AU  - Renner, T.J.*
AU  - Warnke, A.*
AU  - Romanos, M.*
AU  - Lesch, K.P.*
AU  - Reif, A.*
AU  - Schimmelmann, B.G.*
AU  - Hebebrand, J.*
AU  - Psychiatric GWAS Consortium ADHD Subgroup (*)
C1  - 6813
C2  - 29308
SP  - 888-897
TI  - Genome-wide association study in German patients with attention deficit/hyperactivity disorder.
JO  - Am. J. Med. Genet. B
VL  - 156B
IS  - 8
PB  - Wiley-Blackwell
PY  - 2011
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5' untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerström index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically.
AU  - Mobascher, A.*
AU  - Rujescu, D.*
AU  - Mittelstraß, K.
AU  - Giegling, I.*
AU  - Lamina, C.
AU  - Nitz, B.
AU  - Brenner, H.*
AU  - Fehr, C.*
AU  - Breitling, L.P.*
AU  - Gallinat, J.*
AU  - Rothenbacher, D.*
AU  - Raum, E.*
AU  - Müller, H.*
AU  - Ruppert, A.*
AU  - Hartmann, A.M.*
AU  - Möller, H.J.*
AU  - Gal, A.*
AU  - Gieger, C.
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Dahmen, N.*
AU  - Winterer, G.*
C1  - 3236
C2  - 27301
SP  - 684-690
TI  - Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2) with nicotine addiction.
JO  - Am. J. Med. Genet. B
VL  - 153B
IS  - 2
PB  - Wiley-Blackwell
PY  - 2010
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "co nition enhancement.'' Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly'' and the verbal subtest "similarities.'' In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression.
AU  - Winterer, G.*
AU  - Mittelstraß, K.
AU  - Giegling, I.*
AU  - Lamina, C.
AU  - Fehr, C.*
AU  - Brenner, H.*
AU  - Breitling, L.P.*
AU  - Nitz, B.
AU  - Raum, E.*
AU  - Müller, H.*
AU  - Gallinat, J.*
AU  - Gal, A.*
AU  - Heim, K.
AU  - Prokisch, H.
AU  - Meitinger, T.
AU  - Hartmann, A.M.*
AU  - Möller, H.J.*
AU  - Gieger, C.
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Dahmen, N.*
AU  - Rujescu, D.*
C1  - 5235
C2  - 28124
CY  - Hoboken
SP  - 1448-1458
TI  - Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance.
JO  - Am. J. Med. Genet. B
VL  - 158B
IS  - 8
PB  - Wiley-Blackwell
PY  - 2010
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Results from molecular and pharmacological studies point to involvement of the gene coding for the phosphatidylinositol-4-phosphate 5-kinase type II-alpha (PIP5K2A) in the development of schizophrenia and bipolar affective disorder (BPAD). The PIP5K2A gene locus, which is located on chromosomal region 10p12, has been implicated in the development of both disorders by independent linkage and association studies. On a cellular level, PIP5K2A is an enzyme component of the metabolism of inositol phosphate, which has been considered a potential target for the therapeutic action of lithium in BPAD patients. Given that the PIP5K2A gene is a promising candidate for the development of both disorders, we performed an association study between genetic variants at the PIP5K2A locus and 268 patients with schizophrenia, 260 patients with BPAD and 325 ethnically matched healthy controls. We failed to detect association to either disorder using PIP5K2A gene variants through single-marker and haplotype analysis. Therefore, our data does not support an involvement of the PIP5K2A locus in the etiology of either schizophrenia or BPAD in the German population. © 2006 Wiley-Liss, Inc.
AU  - Jamra, R.A.*
AU  - Klein, K.*
AU  - Villela, A.W.*
AU  - Becker, T.*
AU  - Schulze, T.G.*
AU  - Schmael, C.*
AU  - Deschner, M.*
AU  - Klopp, N.
AU  - Illig, T.
AU  - Propping, P.*
AU  - Cichon, S.*
AU  - Rietschel, M.*
AU  - Nöthen, M.M.*
AU  - Schumacher, J.*
C1  - 5095
C2  - 24264
SP  - 663-665
TI  - Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder.
JO  - Am. J. Med. Genet. B
VL  - 141B
IS  - 6
PB  - Wiley
PY  - 2006
SN  - 1552-4841
ER  - 

TY  - JOUR
AB  - Schizophrenia or schizoaffective disorders are quite common features in patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS) as a result of hemizygosity of chromosome 22q11.2. We evaluated the PCQAP gene, which maps within the DGS/VCFS interval, as a potential candidate for schizophrenia susceptibility. PCQAP encodes for a subunit of the large multiprotein complex PC2, which exhibits a coactivator function in RNA polymerase II mediated transcription. Using a case–control study, we searched association between schizophrenia and the intragenic coding trinucleotide polymorphism. The distribution of the CAG repeat alleles was significantly different between patients and controls with the Mann-Whitney test (z = −2.5694, P = 0.0051; schizophrenics: n = 378, W = 161,002.5, Mean rank = 425.9325; controls: n  = 444, W = 177,250.5, Mean rank = 399.2128). This result may indicate a possible involvement of the multiprotein complex PC2 in schizophrenia susceptibility.
AU  - de Luca, A.*
AU  - Conti, E.*
AU  - Grifone, N.*
AU  - Amati, F.*
AU  - Spalletta, G.*
AU  - Caltagirone, C.*
AU  - Bonaviri, G.*
AU  - Pasini, A.*
AU  - Gennareli, M.*
AU  - Stafano, B.*
AU  - Berti, L.
AU  - Mittler, G.
AU  - Meisterernst, M.
AU  - Dallapiccola, B.*
AU  - Novelli, G.*
C1  - 22383
C2  - 21298
SP  - 32-35
TI  - Association Study Between CAG Trinucleotide Repeats in the PCQAP Gene (PC2 Glutamine/Q- Rich-Associated Protein) and Schizophrenia.
JO  - Am. J. Med. Genet. B
VL  - 116
IS  - 1
PY  - 2003
SN  - 1552-4841
ER  -