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Brion S Maher

Publications and source records attributed to Brion S Maher.

At least 19 recordsLinked to original sources
PubMed2006

Minor physical anomalies in schizophrenia: a meta-analysis.

Numerous studies report an increased frequency of minor physical anomalies (MPAs) in schizophrenic individuals compared with controls. However, these studies vary considerably regarding the magnitude of the case-control disparity and the topographical distribution of the anomalies. A meta-analysis was carried out on the existing MPA literature in an effort to better understand the relationship between MPAs and schizophrenia. Following a literature search, 13 studies were identified that met our inclusion criteria. Mean total MPA scores were available for 11 of these studies, whereas only seven studies provided regional MPA scores. For both the total MPA and regional MPA analyses, pooled effect sizes (Hedges' g and pooled odds ratios, respectively) were calculated along with tests of heterogeneity. For the total MPA analyses, a meta-regression approach was used to explore the relationship between possible moderator variables (e.g., number of MPA scale items) and effect size heterogeneity. The magnitude of the pooled effect size for the total MPA scores was high (1.131; p<0.001), indicating significantly more overall MPAs in schizophrenic individuals. Significant effect size heterogeneity was present (p<0.001); however, this heterogeneity could not be explained by any of the included moderator variables. The regional MPA analysis revealed significantly increased MPAs in all six anatomical regions (p<0.05), although the pooled odds ratios for these regions did not differ significantly from one another. These results suggest a lack of regional specificity for MPAs in schizophrenia.

Adult↗
PubMed2006

Genome survey for loci that influence successful aging: results at 10-cM resolution.

OBJECTIVE: A systematic genome survey was initiated to identify loci that affect the likelihood of reaching age 90 with preserved cognition (successful aging). METHODS: The genome survey was conducted at 10-cM resolution for simple sequence tandem repeat polymorphisms (SSTRPs) that identify genes for Successful AGing (SAG loci) by virtue of linkage disequilibrium. Efficiency was enhanced by genotyping pools of DNA from 100 cognitively intact elders and 100 young (18-25 years) adults. The comparison groups included equal numbers of white men and women of similar ethnicity that were recruited from the southwestern Pennsylvania region. RESULTS: Our genome survey identified nine SAG candidate loci that may influence the likelihood of reaching age 90 or more with preserved cognition. Two of the autosomal SAG loci revealed stronger allelic associations with successful aging in men than women (D1S1728, D8S264) and two were located on sex chromosomes (DXS9902, DYS390). DXS9902 resides within a predicted gene, whereas six of the SAG loci are located within regions previously reported to show linkage to other phenotypes. CONCLUSIONS: The results of our study suggest that loci with differential effects on the successful aging of men and women may be common. The majority of the SAG candidate loci detected in this study overlap with regions previously reported to show linkage to susceptibility genes for cardiovascular disorders, psychiatric disorders, and the accumulation of tissue damage resulting from oxidative stress.

Adolescent↗
PubMed2006

Nicotine metabolizing genes GSTT1 and CYP1A1 in sudden infant death syndrome.

Exposure to tobacco, both to the developing fetus as well as in the postnatal period, has been identified as a key risk factor in the etiology of sudden infant death syndrome (SIDS). Polymorphisms in both the GSTT1 and CYP1A1 genes have been reported to impact the metabolic detoxification process for cigarette smoke and have been associated with low birth weight. Thus, expression of polymorphisms in these genes may account for the varying susceptibility to the adverse health consequences of tobacco exposure, including SIDS. We hypothesized that functional polymorphisms in GSTT1 (gene deletion) and CYP1A1 (m1, m2, and m3) might be associated with SIDS risk. DNA was prepared from 106 SIDS cases and 106 ethnicity- and gender-matched controls using standard methods. Regions of interest were amplified using PCR, subjected to enzyme digestion, and analyzed on agarose gel. No association was observed between the GSTT1 gene deletion or the CYP1A1 m1, m2, and m3 polymorphisms with SIDS risk when considered independently or in combination. These results indicate that the GSTT1 gene deletion and polymorphisms of CYP1A1 are not responsible for increased SIDS risk in our dataset. However, because SIDS cases with confirmed history of nicotine exposure were limited (7/106 cases), a relationship that might be apparent in a cohort with a large subset of SIDS cases with known history of nicotine exposure cannot be ruled out. A prospective study of SIDS cases with nicotine exposure history is necessary to resolve the relationship between nicotine metabolizing genes and SIDS.

Case-Control Studies↗
PubMed2005

Methods for detecting gene x gene interaction in multiplex extended pedigrees.

Complex diseases are multifactorial in nature and can involve multiple loci with gene x gene and gene x environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene x gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem.

Epistasis, Genetic↗
PubMed2005

Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations.

In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6-7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160-167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287-294 cM, including D2), chromosome 5 (p-value < 0.001 for 0-7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7-14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage.

Chromosomes, Human↗
PubMed2005

Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology.

Congenital central hypoventilation syndrome (CCHS) is caused by mutations in PHOX2B, which is essential for maturation of the neural crest into the autonomic nervous system and is expressed in the dorsal rhombencephalon, a region that gives rise to facial structures. Digital photographs of 45 individuals with PHOX2B-confirmed CCHS, and 45 matched controls were analyzed for 17 linear and 6 angular measurements, and 9 derived indices. Paired t tests were used to compare group means, correlation was calculated between PHOX2B polyalanine expansion number and facial measures, and stepwise logistic regression was used to predict case-control and genotype status. CCHS cases differed significantly from controls on 13 variables (6 after p value correction: nasolabial angle, upper lip height, lateral lip height, facial index, upper facial index, and presence of inferior inflection of the lateral segment of the upper lip vermillion border). Five variables were able to predict correctly 85.7% of CCHS cases and 82.2% of controls: upper lip height, biocular width, upper facial height, nasal tip protrusion, and inferior inflection of the upper lip vermillion border. A negative relationship between number of repeats and four anthropometric measures was observed: mandible breadth, nasolabial angle, lateral lip height, and mandible-face width index. These results suggest a characteristic facial phenotype in children and young adults with CCHS, due to an expansion mutation in PHOX2B.

Adolescent↗
PubMed2005

Approaches to detecting gene x gene interaction in Genetic Analysis Workshop 14 pedigrees.

Whether driven by the general lack of success in finding single-gene contributions to complex disease, by increased knowledge about the potential involvement of specific biological interactions in complex disease, or by recent dramatic increases in computational power, a large number of approaches to detect locus x locus interactions were recently proposed and implemented. The six Genetic Analysis Workshop 14 (GAW14) papers summarized here each applied either existing or refined approaches with the goal of detecting gene x gene, or locus x locus, interactions in the GAW14 data. Five of six papers analyzed the simulated data; the other analyzed the Collaborative Study on the Genetics of Alcoholism data. The analytic strategies implemented for detecting interactions included multifactor dimensionality reduction, conditional linkage analysis, nonparametric linkage correlation, two-locus parametric linkage analysis, and a joint test of linkage and association. Overall, most of the groups found limited success in consistently detecting all of the simulated interactions due, in large part, to the nature of the generating model.

Alcoholism↗
PubMed2005

Dental school applicants' use of website information during the application process.

The University of Pittsburgh's School of Dental Medicine (SDM) is a medium-sized, private, state-related dental school. As other schools have done recently, the SDM made a substantial effort to upgrade its website in 2003. Internal satisfaction and anecdotal data notwithstanding, there is no measure of the website's usefulness in attracting applicants. We designed an anonymous survey of twenty-one questions in an effort to better understand what kinds of information sources our applicants used to make their application decisions; which information they perceived as useful during each phase of the overall application process; how they ranked our website compared to those of other dental schools that they considered; and what they thought could make our website better. Our study supports the notion that applicants rely in part on dental school websites during the application process. Data from this study point to the areas that are of most interest to applicants when they visit a dental school website. This information could help dental school administrators determine the effort they should spend on their school's website as an advertising and recruitment tool. We recommend that dental schools make the most important application-related information and criteria easy to find.

Advertising↗
PubMed2004

Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.

BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

Cleft Lip↗
PubMed2004

Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression.

We previously described the results of a genome-wide linkage survey for genetic loci that influenced the development of unipolar mood disorders in 81 families identified by individuals with Recurrent, Early-Onset, Major Depressive Disorder (RE-MDD) [Zubenko et al. 2003b; Am J Med Genet (Neuropsychiatr Genet) 123B:1-18]. In the current study, we extended this linkage analysis by including the history of a suicide attempt as a covariate to identify chromosomal regions that harbor genes that influence the risk of this behavior in the context of mood disorders. This approach identified six linkage peaks with maximum multipoint DeltaLOD scores that reached genome-wide adjusted levels of significance (2p, 5q, 6q, 8p, 11q, and Xq). Four of these (2p, 6q, 8p, and Xq) exceeded the criterion for "highly-significant linkage" (genome-wide adjusted P < 0.001) recommended by Lander and Kruglyak [1995; Nat Genet 11:241-246]. The strongest evidence for linkage was observed in analyses employing affected relative pairs (ARPs) with the most severe and disabling Mood Disorders: Depression Spectrum Disorder and RE-MDD. The highest DeltaLOD score that emerged from this linkage analysis, 5.08, occurred for ARPs with Depression Spectrum Disorder at D8S1145 (37.0 cM, 18.2 Mbps, P < 0.0001) at cytogenetic location 8p22-p21. Significant linkage results on Xq arose from analyses of ARPs with RE-MDD at DXS1047 (143 cM, 127.8 Mbps, DeltaLOD = 3.87, P < 0.0001), a finding that may contribute to the higher rate of suicide attempts among women than men. These findings provide evidence for suicide risk loci that are independent of susceptibility loci for Mood Disorders, and suggest that the capacity for suicide risk loci to affect the development of suicidal behavior depends on the psychiatric disorder or subtype with which they interact.

Age of Onset↗
PubMed2004

Sudden infant death syndrome: case-control frequency differences at genes pertinent to early autonomic nervous system embryologic development.

We have previously identified polymorphisms in the serotonin transporter gene promoter region and in intron 2 that were more common among sudden infant death syndrome (SIDS) cases compared with control subjects. To elucidate further the genetic profile that might increase an infant's vulnerability to SIDS, we focused on the recognized relationship between autonomic nervous system (ANS) dysregulation and SIDS. We therefore studied genes pertinent to early embryologic development of the ANS, including MASH1, BMP2, PHOX2a, PHOX2b, RET, ECE1, EDN1, TLX3, and EN1 in 92 probands with SIDS and 92 gender- and ethnicity-matched control subjects. Eleven protein-changing rare mutations were identified in 14 of 92 SIDS cases among the PHOX2a, RET, ECE1, TLX3, and EN1 genes. Only 1 of these mutations (TLX3) was identified in 2 of 92 control subjects. Black infants accounted for 10 of these mutations in SIDS cases and 2 control subjects. Four protein-changing common polymorphisms were identified in BMP2, RET, ECE1, and EDN1, but the allele frequency did not differ between SIDS cases and control subjects. However, among SIDS cases, the allele frequency for the BMP2 common polymorphism demonstrated ethnic differences; among control subjects, the allele frequency for the BMP2 and the ECE1 common polymorphisms also demonstrated ethnic differences. These data represent further refinement of the genetic profile that might place an infant at risk for SIDS.

Autonomic Nervous System↗
PubMed2004

Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35.

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.

Chromosomes, Human, Pair 2↗
PubMed2004

Genetic analysis of candidate loci in non-syndromic cleft lip families from Antioquia-Colombia and Ohio.

Non-syndromic cleft lip with or without cleft palate (CL/P) is a genetically complex birth defect, with a prevalence from 1/500 to 1/1,000 live births. Evidence from linkage and linkage disequilibrium studies is contradictory suggesting that heterogeneity between study populations may exist. A recent report of a genome widescan in 92 sib pairs from the United Kingdom revealed suggestive linkage to 10 loci [Prescott et al., 2000]. The purpose of this study is to replicate those results and evaluate additional candidate genes in 49 Colombian and 13 Ohio families. Genotypes were obtained for STRPs at 1p36, 2p13 (TGFA), 4p16 (MSX1), 6p23-25, 6q25-27, 8q23-24, 11p12-q13, 12q13, 14q24 (TGFB3), 16q22-24, 17q12-21 (RARA), and Xcen-q21. Linkage was performed using parametric (dominant and recessive models) and non-parametric (GenehunterNPL and SimIBD) analyses. In addition, heterogeneity was analyzed using GenehunterHLOD, and association determined by the TDT. The Colombian families showed significant SimIBD results for 11p12-q13 (P = 0.034), 12q13 (P = 0.015), 16q22-24 (0.01), and 17q12-21 (0.009), while the Ohio families showed significant SimIBD results for 1p36 (P = 0.02), TGFA (P = 0.005), 6p23 (P = 0.004), 11p12-q13 (P = 0.048) and significant NPL results for TGFA (NPL = 3.01, P = 0.009), 4p16 (MNPL = 2.07, P = 0.03) and 12q13 (SNPL = 3.55, P = 0.007). Significant association results were obtained only for the Colombian families in the regions 1p36 (P = 0.046), 6p23-25 (P = 0.020), and 12q13 (P = 0.046). In addition several families yielded LOD scores ranging from 1.09 to 1.73, for loci at 4p16, 6p23-25, 16q22-24, and 17q13. These results confirm previous reports for these loci. However, the differences between the two populations suggest that population specific locus heterogeneity exists. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.

Cleft Lip↗
PubMed2004

Haplotypes of the monoamine oxidase genes and the risk for substance use disorders.

Monoamine oxidase A (MAOA) locus is an attractive candidate for exploring genetic contribution to the variation in the risk for substance use disorders (SUD) because of its important role in the metabolism of neurotransmitters, including dopamine and serotonin. Prior findings have suggested an association of the MAOA gene with the risk for early onset SUD. To extend this research, we genotyped four MAOA markers (two VNTR polymorphisms and two SNPs) and built a cladogram reflecting the evolutionary history of MAOA haplotypes [Nguyen et al., under review]. The cladogram served as the framework for nested ANOVA and logit analyses of association between MAOA and indices of liability to SUD (diagnosis, age of onset, and a dimensional index of substance use related problems) in a sample of adult males of European ancestry. Whereas no association was found for the categorical diagnosis, a significant relationship was detected between the dimensional liability indices and MAOA haplotypes. Overall, our results, albeit not definitive, are consistent with the hypothesis that variants in MAOA account for a small portion of the variance of SUD risk, possibly mediated by liability to early onset behavioral problems.

Adult↗
PubMed2003

Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b.

Idiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970. A genetic basis of CCHS has been proposed because of the reports of four families with two affected children, because of mother-child transmission, and because of a recent report of a polyalanine expansion mutation in PHOX2b in a subset of CCHS subjects. We, therefore, studied genes pertinent to early embryologic development of the ANS including mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), engrailed-1 (EN1), TLX3, endothelin converting enzyme-1 (ECE1), endothelin-1 (EDN1), PHOX2a, and PHOX2b in 67 probands with CCHS, and gender- and ethnicity-matched controls. No disease-defining mutations were identified in MASH1, BMP2, EN1, TLX3, ECE1, EDN1, or PHOX2a. The 65/67 CCHS probands (97%) were found to be heterozygous for the exon 3 polyalanine expansion mutation identified previously in PHOX2b. Further, there was an association between repeat mutation length and severity of the CCHS/ANSD phenotype. Of the two probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 which truncated the protein and the other had no mutation in PHOX2b but had a previously reported EDN3 frameshift point mutation. The polyalanine expansion mutation was not found in any of 67 matched controls. Of 54 available families (including 97 unaffected parents), whose child carried the PHOX2b mutation, 4 parents demonstrated mosaicism for an expansion mutation identical to that seen in the CCHS cases, suggesting that not all mutations in affected probands with unaffected parents are de novo. We also studied four women with CCHS who were heterozygous for the PHOX2b mutation, each with one child. Three of the four children were also affected and had the same mutation, demonstrating autosomal dominant inheritance of the mutation. Assay of the PHOX2b polyalanine repeat mutation represents a highly sensitive and specific technique for confirming the diagnosis of CCHS. Identification of the CCHS mutation will lead to clarification of the phenotype, allow for prenatal diagnosis for parents of CCHS probands and adults with CCHS in future pregnancies, and potentially direct intervention strategies for the treatment of CCHS.

Adolescent↗