RESUMO
CONTEXT: Neuroticism is a trait that reflects a tendency toward negative mood states. It has long been linked to internalizing psychiatric conditions, such as anxiety and depression, and it accounts for much of the substantial comorbidity seen between these disorders. OBJECTIVE: To identify common genetic variants that affect neuroticism to better understand (the comorbidity between) a broad range of psychiatric disorders and to develop effective treatments. DESIGN, SETTING, AND PARTICIPANTS: More than 420,000 genetic markers were tested for their association with neuroticism in a genomewide association study (GWAS). The GWAS sample consisted of 1227 healthy individuals ascertained from a US national sampling frame and available from the National Institute of Mental Health genetics repository. The most promising markers were subsequently tested in a German replication sample comprising 1880 healthy individuals. MAIN OUTCOME MEASURES: A strict definition of replication (same marker, same direction of effects, and same measure) combined with a threshold we proposed previously for declaring significance in genetic studies that ensures a mean probability of producing false-positive findings of less than 10%. RESULTS: The most promising results in the GWAS and replication samples were single-nucleotide polymorphisms (SNPs) in the gene MAMDC1. These SNPs all tagged the same 2 haplotypes and had P values of 10(-5) to 10(-6) in the GWAS sample and of .006 to .02 in the replication sample. Furthermore, the replication involved the same SNPs and the same direction of effects. In a combined analysis of all data, several SNPs were significant according to the threshold that allows for 10% false-positive findings. CONCLUSIONS: The small effect sizes may limit the prognostic, diagnostic, and therapeutic use of SNP markers such as those in MAMDC1. However, the present study demonstrates the potential of a GWAS to discover potentially important pathogenic pathways for which clinically more powerful (bio)markers may eventually be developed.
Assuntos
Replicação do DNA/genética , Expressão Gênica/genética , Genoma , Glicosilfosfatidilinositóis/genética , Transtornos Neuróticos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: A comprehensive understanding of the etiology and neurobiology of nicotine dependence is not available. We sought to identify genomic regions that might contain etiologically-relevant loci using genomewide univariate and bivariate linkage analyses. METHODS: We conducted secondary data analyses of 626 all possible sibling pairs ascertained in Ireland and Northern Ireland on the basis of alcohol dependence. A set of 1020 short tandem repeat genetic markers were genotyped in all subjects. The phenotypes analyzed were the Fagerström Test for Nicotine Dependence (FTND), a history of nicotine dependence, the number of symptoms of alcohol dependence (AlcSx), and a history of alcohol dependence. Genomewide linkage analyses were conducted with non-parametric and variance components methods. FINDINGS: For the bivariate variance component analysis of the continuous FTND and AlcSx scores, multipoint LOD scores were >4 in two genomic regions--an 11cM region on chr7 (D7S2252-D7S691, empirical p=0.0006) and an 8cM region on chr18 flanking D18S63 (empirical p=0.0007). These findings did not exceed a conservative estimate of study-wide significance. The remaining sets of findings had considerably smaller or less consistent peak signals. Notably, strong linkage signal at D4S1611 for AlcSx from a prior report (PMID 16534506) was not found when jointly analyzed with FTND. INTERPRETATION: Replication is required. However, chromosomes 7 and 18 may contain genetic loci relevant to the etiology of nicotine-related phenotypes.
Assuntos
Tabagismo/genética , Tabagismo/psicologia , Adulto , Idoso , Alcoolismo/complicações , Alcoolismo/epidemiologia , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 7/genética , Coleta de Dados , Feminino , Ligação Genética/genética , Humanos , Irlanda/epidemiologia , Desequilíbrio de Ligação , Escore Lod , Masculino , Pessoa de Meia-Idade , Irlanda do Norte/epidemiologia , Fenótipo , Sequências de Repetição em Tandem , Tabagismo/complicaçõesRESUMO
The purpose of this study was to detect genetic loci that influence clinical features of, but not necessarily susceptibility to, psychotic illness. In the Irish Study of High-Density Schizophrenia Families (n = 270 families, n = 1,408 individuals), subjects with non-affective psychosis were rated using the Operational Criteria Checklist for Psychotic Illness. Factor analysis identified hallucinations, delusions, and negative, manic, and depressive symptom factors. We performed autosomal genome-wide multipoint non-parametric quantitative trait locus linkage analysis, in affected individuals only, using these five factors, as well as age at onset, and course of illness. Determination of empirical significance and correction for multiple testing was implemented using 200 simulated genome scans. We also tested for pleiotropic loci by examining the sums of -log(10)'s of the empirical P values of multiple traits in selected regions. LODs of 2.42 and 2.35 were obtained near D9S934 (9q33.1) and D14S587 (14q24.2), respectively, for course of illness, and of 2.26 between D6S1040-D6S2420 (6q23.1-25.1) and age at onset. No other regions met criteria for suggestive linkage to any one trait. No loci were significant after correction for multiple testing. On 6q, however, the joint linkage of age of onset, course, delusions, and depressive symptoms resulted in a genome-wide P = 0.06. We conclude that genes located near 9q33.1 and 14q24.2 may modify the clinical course and severity of schizophrenia. A gene in 6q may affect several clinical features of illness.
Assuntos
Fenótipo , Locos de Características Quantitativas , Esquizofrenia/genética , Estudos de Coortes , Manual Diagnóstico e Estatístico de Transtornos Mentais , Modificador do Efeito Epidemiológico , Análise Fatorial , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Entrevista Psicológica , Irlanda/epidemiologia , Escore Lod , Masculino , Esquizofrenia/epidemiologiaRESUMO
BACKGROUND: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)? METHODS: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short-tandem-repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus. RESULTS: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32. CONCLUSIONS: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.