Biomedical subjects

Valentina Moskvina

Publications and source records attributed to Valentina Moskvina.

At least 19 recordsLinked to original sources

PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗

PubMed2007

Interrelationship of childhood trauma, neuroticism, and depressive phenotype.

Both childhood trauma (CT) and genetic factors contribute to the pathophysiology of depression. We studied the relationship of CT to age of onset (AO) of depression, personality traits, and expression of symptom dimensions in 324 adults with recurrent unipolar depression. Subjects received structured psychiatric interviews and completed CT, depressive symptom, and personality rating questionnaires. Experience of at least one type of trauma was reported by 79.9% of subjects, and the most common forms of trauma were physical neglect, emotional abuse, and emotional neglect. There was an earlier AO of depression in the groups that reported CT compared to those that reported none, with earliest AO occurring in those who had experienced the highest levels of CT. There were no significant correlations between overall CT scores and neuroticism or extraversion. Total CT was a significant (P=.008) predictor of the Mood symptom dimension, mostly accounted for by emotional abuse (P=.019), and physical neglect predicted the Anxiety symptom dimension (P=.002). All types of CT are commonly reported in individuals with depression, and emotional abuse and physical neglect, though previously less well identified, appear to have an important role in the pathogenesis of depressive disorders. The effect of CT on individuals with an underlying genetic vulnerability to depression may result in differences in depressive phenotype characterized by earlier AO of depression and the expression of specific depressive symptom dimensions.

Adolescent↗

PubMed2006

Individual SNP allele reconstruction from informative markers selected by a non-linear Gauss-type algorithm.

OBJECTIVES: In view of the linkage disequilibrium structure of the genome, the selection of maximally informative SNP markers is a fundamental issue in the design of association studies. Currently used selection methods rely on pairwise marker correlation or informativity measures for subsets of markers. Nevertheless, the selected markers do not provide a completely satisfactory description of the individual remaining markers. The number of tag markers can be further reduced by using haplotypic information, but then the results of association analysis are difficult to interpret. METHODS AND RESULTS: We propose a non-linear Gauss-type algorithm selecting a subset of markers which is optimal with respect to the informativity measures and allows an explicit reconstruction of all other known markers, thus permitting direct inference of allelic association. The selection is based on the haplotype distribution in the population, but can be adapted to work with unphased genotypes directly. CONCLUSIONS: The proposed algorithm provides a rational methodology of informative marker selection, allowing for control and optimisation of information content and full marker reconstruction. Moreover, the reconstruction step can also be applied to tag markers selected using a different method at the stage of study design, identifying those markers which cannot be uniquely recovered from the chosen tags.

Algorithms↗

PubMed2006

Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2006

Analysis of ProDH, COMT and ZDHHC8 risk variants does not support individual or interactive effects on schizophrenia susceptibility.

Synergistic interaction between genes on chromosome 22q11 recently has been proposed as a possible mechanism which could confer increased risk for schizophrenia. Based on this hypothesis, our study aimed to explore main, cis- and trans-interacting effects of three candidate genes on 22q11, ProDH, COMT and ZDHHC8. We selected four putative risk variants, residing within these genes, ProDH 1945, ProDH 2026, COMT ValMet and ZDHHC8 rs175174, and studied these in a large family-based schizophrenia association sample of European origin (488 Bulgarian parent-offspring trios). The presence of interaction between the variants was tested by conditional logistic regression analysis based on a case-pseudocontrol design. Our study did not find statistical evidence for allelic (investigation of ProDH markers only), genotypic, haplotypic, or interactive effects between ProDH, COMT and ZDHHC8. Our data do not support the hypothesis that an interaction between these genes influences susceptibility to schizophrenia.

Acyltransferases↗

PubMed2006

Metyrapone improves endothelial dysfunction in patients with treated depression.

OBJECTIVES: This study sought to examine the effect of metyrapone on endothelial dysfunction in patients with treated recurrent major depression. BACKGROUND: Depression is an independent risk factor for the development of coronary heart disease, and patients with depression have endothelial dysfunction, an atherogenic abnormality. This abnormality may be attributable to abnormal hypothalamic-pituitary-adrenal (HPA) axis function, a feature of depression, resulting in increased exposure to cortisol. Cortisol administration produces endothelial dysfunction in healthy subjects. METHODS: We measured endothelial function using flow-mediated dilation (FMD) of the brachial artery in 30 patients with depression and in 36 matched control subjects. Patients were randomized (double blind) to metyrapone (an inhibitor of cortisol synthesis) or placebo, and FMD was remeasured 6 h later. RESULTS: At baseline, FMD was impaired in patients versus control subjects (mean [standard error]), -1.27% [0.91%] vs. 4.37% [0.59%] (p < 0.001). The FMD was similar in the placebo and the metyrapone patient groups at baseline (0.17% [1.04%] vs. -2.72% [1.30%], p = 0.11). Metyrapone significantly reduced plasma cortisol levels. There was a significant improvement in FMD in the metyrapone group from -2.72% [1.30%] to 3.82% [0.99%] (p < 0.001), whereas the change in the placebo group, from 0.17% [1.04%] to 1.15% [1.14%], was not significant. Analysis of covariation showed that the effect of metyrapone was significant (p = 0.034). CONCLUSIONS: Inhibition of cortisol production by metyrapone ameliorates the endothelial dysfunction seen in depression, suggesting that the mechanism of the endothelial dysfunction may involve cortisol.

Adult↗

PubMed2006

Assessment of the relationship between pre-chip and post-chip quality measures for Affymetrix GeneChip expression data.

BACKGROUND: Gene expression microarray experiments are expensive to conduct and guidelines for acceptable quality control at intermediate steps before and after the samples are hybridised to chips are vague. We conducted an experiment hybridising RNA from human brain to 117 U133A Affymetrix GeneChips and used these data to explore the relationship between 4 pre-chip variables and 22 post-chip outcomes and quality control measures. RESULTS: We found that the pre-chip variables were significantly correlated with each other but that this correlation was strongest between measures of RNA quality and cRNA yield. Post-mortem interval was negatively correlated with these variables. Four principal components, reflecting array outliers, array adjustment, hybridisation noise and RNA integrity, explain about 75% of the total post-chip measure variability. Two significant canonical correlations existed between the pre-chip and post-chip variables, derived from MAS 5.0, dChip and the Bioconductor packages affy and affyPLM. The strongest (CANCOR 0.838, p < 0.0001) correlated RNA integrity and yield with post chip quality control (QC) measures indexing 3'/5' RNA ratios, bias or scaling of the chip and scaling of the variability of the signal across the chip. Post-mortem interval was relatively unimportant. We also found that the RNA integrity number (RIN) could be moderately well predicted by post-chip measures B_ACTIN35, GAPDH35 and SF. CONCLUSION: We have found that the post-chip variables having the strongest association with quantities measurable before hybridisation are those reflecting RNA integrity. Other aspects of quality, such as noise measures (reflecting the execution of the assay) or measures reflecting data quality (outlier status and array adjustment variables) are not well predicted by the variables we were able to determine ahead of time. There could be other variables measurable pre-hybridisation which may be better associated with expression data quality measures. Uncovering such connections could create savings on costly microarray experiments by eliminating poor samples before hybridisation.

Artifacts↗

PubMed2006

Effects of differential genotyping error rate on the type I error probability of case-control studies.

OBJECTIVES: It is well known that genotyping error adversely affects the power of genetic case-control association studies but there is little research on its effects on type I error, and none that has addressed possible differences in genotype error rates between cases and controls. METHODS: We used simulations to examine the influence of genotyping error on the type I error probability given by case-control studies. The effect of genotyping error on the magnitude of type I error was explored for a single marker of varying minor allele frequency (MAF), and for haplotypic tests based on two markers with varying MAF and linkage disequilibrium (LD) measure r(2). RESULTS: We show that even with low genotyping error rates (<0.01), systematic differences in the error rate between samples can result in type I error rates substantially above 0.05. The effect was maximal for markers with small MAF, markers in strong LD, and where a common allele is more frequently misclassified as a rare allele than vice versa. The problem was also exacerbated by the use of large samples. CONCLUSIONS: Our results show that small differential genotyping error rates between cases and controls pose significant problems for association analyses. Differential genotyping error rates are particularly likely to arise where genotype data are combined from multiple sites, or where case genotypes are examined against archived reference population cohort genotypes that are being generated in several countries. Although these strategies may be necessary to obtain adequately powered samples, our data show the importance of stringent quality control. Furthermore, associations based on rare haplotypes should be treated with caution.

Alleles↗

PubMed2006

Pooled DNA genotyping on Affymetrix SNP genotyping arrays.

BACKGROUND: Genotyping technology has advanced such that genome-wide association studies of complex diseases based upon dense marker maps are now technically feasible. However, the cost of such projects remains high. Pooled DNA genotyping offers the possibility of applying the same technologies at a fraction of the cost, and there is some evidence that certain ultra-high throughput platforms also perform with an acceptable accuracy. However, thus far, this conclusion is based upon published data concerning only a small number of SNPs. RESULTS: In the current study we prepared DNA pools from the parents and from the offspring of 30 parent-child trios that have been extensively genotyped by the HapMap project. We analysed the two pools with Affymetrix 10 K Xba 142 2.0 Arrays. The availability of the HapMap data allowed us to validate the performance of 6843 SNPs for which we had both complete individual and pooled genotyping data. Pooled analyses averaged over 5-6 microarrays resulted in highly reproducible results. Moreover, the accuracy of estimating differences in allele frequency between pools using this ultra-high throughput system was comparable with previous reports of pooling based upon lower throughput platforms, with an average error for the predicted allelic frequencies differences between the two pools of 1.37% and with 95% of SNPs showing an error of < 3.2%. CONCLUSION: Genotyping thousands of SNPs with DNA pooling using Affymetrix microarrays produces highly accurate results and can be used for genome-wide association studies.

Alleles↗

PubMed2006

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.

Adult↗

PubMed2006

Convergent evidence for 2',3'-cyclic nucleotide 3'-phosphodiesterase as a possible susceptibility gene for schizophrenia.

CONTEXT: Convergent data make 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) a candidate gene for schizophrenia. Reduced expression has been reported in the schizophrenic brain. The CNP gene maps to a region to which we have reported linkage to schizophrenia. Mice in which the CNP gene has been knocked out display central nervous system pathological characteristics reminiscent of some features observed in schizophrenia. 2',3'-Cyclic nucleotide 3'-phosphodiesterase is used as a marker of myelin-forming cells and is detectable in cells of oligodendrocyte lineage throughout life. Because CNP is thought to be important for oligodendrocyte function, altered expression has been interpreted as supportive of the hypothesis that altered oligodendrocyte function may be an etiological factor in schizophrenia. However, it is unclear whether the observed changes in the schizophrenic brain are primary or secondary. OBJECTIVES: To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia. DESIGN: Allele-specific messenger RNA expression assay and genetic association studies. SETTING: Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services. PARTICIPANTS: We used brain tissue from 60 anonymous individuals with no known psychiatric disorder; a case-control sample of 708 white individuals from the United Kingdom meeting DSM-IV criteria for schizophrenia matched for age, sex, and ethnicity to 711 blood donor controls; and a pedigree with DNA from 6 affected siblings and 1 parent, showing evidence for linkage to CNP. MAIN OUTCOME MEASURES: Association between allele and gene expression. Association between allele and schizophrenia. RESULTS: The exonic single nucleotide polymorphism rs2070106 was associated with CNP expression (P<.001). Compatible with underexpression of CNP messenger RNA in schizophrenia, the lower-expressing A allele was significantly associated with schizophrenia (P = .04) in the case-control sample. All affected individuals in the linked pedigree were homozygous for the lower-expression allele, providing independent support for the association (P = .03). CONCLUSIONS: Our data support the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2006

Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer's disease.

OBJECTIVES: To investigate behavioral components of Alzheimer's disease (AD) and to analyze behavioral components in relation to disease severity, apolipoprotein E genotype (APOE), sex, years of education, age at onset, and cognitive impairment. DESIGN: Cross-sectional study. SETTING: Data were collected from community-dwelling individuals and those residing in nursing homes. PARTICIPANTS: A total of 1,120 individuals meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for late-onset probable AD. MEASUREMENTS: Behavioral symptoms were assessed using the Neuropsychiatric Inventory. First-order polychoric correlations, controlling for disease severity, between the 12 symptom domain scores were estimated, and the resulting matrix underwent principal components analysis. RESULTS: Four interpretable components were identified: behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability). Scores on the four components were associated with severity of cognitive impairment. Higher behavioral dysfunction, agitation, and mood component scores were associated with lower age at onset. Behavioral dysfunction and mood component scores were associated with sex. None of the components were associated with age at assessment, years of education, or number of APOE epsilon4 alleles. CONCLUSION: Four behavioral components were identified that were comparable with those observed previously. Future analysis of these components will strengthen understanding of the underlying pathology of behavioral symptoms and AD.

Age of Onset↗

PubMed2006

Susceptibility of biallelic haplotype and genotype frequencies to genotyping error.

With the availability of fast genotyping methods and genomic databases, the search for statistical association of single nucleotide polymorphisms with a complex trait has become an important methodology in medical genetics. However, even fairly rare errors occurring during the genotyping process can lead to spurious association results and decrease in statistical power. We develop a systematic approach to study how genotyping errors change the genotype distribution in a sample. The general M-marker case is reduced to that of a single-marker locus by recognizing the underlying tensor-product structure of the error matrix. Both method and general conclusions apply to the general error model; we give detailed results for allele-based errors of size depending both on the marker locus and the allele present. Multiple errors are treated in terms of the associated diffusion process on the space of genotype distributions. We find that certain genotype and haplotype distributions remain unchanged under genotyping errors, and that genotyping errors generally render the distribution more similar to the stable one. In case-control association studies, this will lead to loss of statistical power for nondifferential genotyping errors and increase in type I error for differential genotyping errors. Moreover, we show that allele-based genotyping errors do not disturb Hardy-Weinberg equilibrium in the genotype distribution. In this setting we also identify maximally affected distributions. As they correspond to situations with rare alleles and marker loci in high linkage disequilibrium, careful checking for genotyping errors is advisable when significant association based on such alleles/haplotypes is observed in association studies.

Alleles↗

PubMed2005

Covariate linkage analysis of GAW14 simulated data incorporating subclinical phenotype, sex, population, parent-of-origin, and interaction.

BACKGROUND: We evaluate a method for the incorporation of covariates into linkage analysis using the Genetic Analysis Workshop 14 simulated data. Focusing on a randomly chosen replicate (42) we investigated the effect of the 12 subclinical phenotypes, sex, population, and parent-of-origin on the linkage signal from a model-free linkage analysis of Kofendrerd Personality Disorder. RESULTS: We detected a linkage peak on chromosome 1, at about 175 cM, which varied depending upon individuals' status for subclinical phenotype b. A linkage peak on chromosome 3 (310 cM) was found not to depend upon subclinical phenotype status. Further peaks were found on chromosomes 5 (12 cM), 9 (4 cM), and 10 (95 cM), depending on the status of subclinical phenotypes a, k, and c/d/g, respectively. CONCLUSION: Retrospective comparison of our results with the simulation model showed correct identification of disease loci D1-5 on chromosomes 1, 3, 5, 9 and 10, respectively.

Chromosome Mapping↗

PubMed2005

Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment.

OBJECTIVES: This study was designed to investigate the role of cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (BRS) by blocking cortisol production with metyrapone before subjecting healthy volunteers to mental stress. BACKGROUND: Mental stress raises cortisol levels and is associated with increased coronary heart disease (CHD) morbidity and mortality, especially from sudden cardiac death. It also causes endothelial dysfunction and impaired BRS. METHODS: We measured brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and BRS in 36 subjects without CHD risk factors who were then randomized in a double-blind fashion to oral metyrapone 750 mg x 2 or placebo. Five hours later we subjected subjects to mental stress and then remeasured endothelial function and BRS. RESULTS: Prestress cortisol levels were significantly higher in the placebo group at 270.5 (30.9) nmol/l versus 89.1 (11.8) nmol/l (p = 0.01), and the increase with stress was higher at 57.9 (17.9) nmol/l versus 11.2 (2.2) nmol/l (p < 0.001). In the placebo group, compared to baseline, FMD and BRS fell significantly from 4.5% (0.7%) to 1.4% (1.1%) (p = 0.02) and 21.4 (2.3) ms/mmHg to 16.3 (1.5) ms/mmHg (p = 0.04), respectively. In the metyrapone group, FMD and BRS were unchanged from baseline: 4.3% (0.9%) versus 5.1% (0.8%) (p = 0.48) and 26.4 (2.9) ms/mmHg versus 24.9 (2.6) ms/mmHg (p = 0.62), respectively. Analysis of covariation showed a significant effect of metyrapone on change in both FMD (p = 0.009) and BRS (p = 0.024). CONCLUSIONS: Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.

Adult↗

PubMed2005

A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder.

BACKGROUND: The glutamatergic system, the major excitatory neurotransmitter system in the central nervous system (CNS) has been proposed as contributing a possible role in the etiology of attention deficit hyperactivity disorder (ADHD). This is based upon observations from animal, neuroimaging, neuroanatomical and neuropsychological studies. Genes related to glutamate function are therefore good functional candidates for this disorder. The SLC1A3 (Solute Carrier Family 1, member 3) gene encodes a glial glutamate transporter which maps to chromosome 5p12, a region of linkage that coincides in two published ADHD genome scans so far. SLC1A3 is thus both a functional and positional candidate gene for ADHD. METHODS: We have undertaken detailed association analysis of SLC1A3 using a multi-stage approach for candidate gene analysis. RESULTS: In a family-based sample (n = 299) we found a significant association between marker rs2269272 (p = .007) and ADHD. Two, two-marker haplotypes, rs2269272/rs3776581 (p = .016) and rs2269272/rs2032893 (p = .013) also yielded evidence of association. CONCLUSIONS: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD.

Adolescent↗

PubMed2005

Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression.

The DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far to identify any specific susceptibility variants and by the absence of any demonstrated function associated with any of the risk haplotypes. In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex. Subsidiary analyses suggest that risk haplotypes identified in other sample groups of white European ancestry also index lower DTNBP1 expression, whereas putative 'protective' haplotypes index high DTNBP1 expression. Our data indicate that variation in the DTNBP1 gene confers susceptibility to schizophrenia through reduced expression, and that this, therefore, represents a primary aetiological mechanism in the disorder.

Adult↗

PubMed2005

Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia.

Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (approximately 2-3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P<.01-.003). After redundant SNPs were excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at P</=.05 were next genotyped in a semi-independent sample of 143 trios of probands with DD and their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P</=.04-.002), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an amino acid (P=.002; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global P=.00001 in the case-control sample; P=.02 in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P=.00003 in the case-control sample; P=.006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown.

Adolescent↗