Publications by authors named "Juan Manuel Peralta"

16 Publications

  • Page 1 of 1

Targeting redox metabolism of the maize-Azospirillum brasilense interaction exposed to arsenic-affected groundwater.

Physiol Plant 2021 Jul 30. Epub 2021 Jul 30.

Instituto de Investigaciones Agrobiotecnológicas - Consejo Nacional de Investigaciones Científicas y Técnicas (INIAB-CONICET), Departamento de Ciencias Naturales, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Córdoba, Argentina.

Arsenic in groundwater constitutes an agronomic problem due to its potential accumulation in the food chain. Among the agro-sustainable tools to reduce metal(oid)s toxicity, the use of plant growth-promoting bacteria (PGPB) becomes important. For that, and based on previous results in which significant differences of As translocation were observed when inoculating maize plants with Az39 or CD Azospirillum strains, we decided to decipher the redox metabolism changes and the antioxidant system response of maize plants inoculated when exposed to a realistic arsenate (As ) dose. Results showed that As caused morphological changes in the root exodermis. Photosynthetic pigments decreased only in CD inoculated plants, while oxidative stress evidence was detected throughout the plant, regardless of the assayed strain. The antioxidant response was strain-differential since only CD inoculated plants showed an increase in superoxide dismutase, glutathione S-transferase (GST), and glutathione reductase (GR) activities while other enzymes showed the same behavior irrespective of the inoculated strain. Gene expression assays reported that only GST23 transcript level was upregulated by arsenate, regardless of the inoculated strain. As diminished the glutathione (GSH) content of roots inoculated with the Az39 strain, and CD inoculated plants showed a decrease of oxidized GSH (GSSG) levels. We suggest a model in which the antioxidant response of the maize-diazotrophs system is modulated by the strain and that GSH plays a central role acting mainly as a substrate for GST. These findings generate knowledge for a suitable PGPB selection, and its scaling to an effective bioinoculant formulation for maize crops exposed to adverse environmental conditions.
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http://dx.doi.org/10.1111/ppl.13514DOI Listing
July 2021

Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation.

Eur Psychiatry 2021 Mar 31;64(1):e29. Epub 2021 Mar 31.

Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation.

Methods: Using data from 9,421 individuals aged 8-21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation.

Results: Externalizing was heritable (h2 = 0.46, p = 1 × 10-6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = -0.412, p = 0.004), verbal reasoning (ρg = -0.485, p = 0.001), spatial reasoning (ρg = -0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10-4), verbal knowledge (ρg = -0.314, p = 0.002), and general cognitive ability (g)(ρg = -0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = -0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing.

Conclusions: Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.
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http://dx.doi.org/10.1192/j.eurpsy.2021.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080212PMC
March 2021

Unraveling the impact of arsenic on the redox response of peanut plants inoculated with two different Bradyrhizobium sp. strains.

Chemosphere 2020 Nov 21;259:127410. Epub 2020 Jun 21.

Instituto de Investigaciones Agrobiotecnológicas - Consejo Nacional de Investigaciones Científicas y Técnicas (INIAB-CONICET), Departamento de Ciencias Naturales, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto (UNRC), Ruta 36, Km 601, X5800, Río Cuarto, Córdoba, Argentina. Electronic address:

Arsenic (As) can be present naturally in groundwater from peanut fields, constituting a serious problem, as roots can accumulate and mobilize the metalloid to their edible parts. Understanding the redox changes in the legume exposed to As may help to detect potential risks to human health and recognize tolerance mechanisms. Thirty-days old peanut plants inoculated with Bradyrhizobium sp. strains (SEMIA6144 or C-145) were exposed to a realistic arsenate concentration, in order to unravel the redox response and characterize the oxidative stress indexes. Thus, root anatomy, reactive oxygen species detection by fluorescence microscopy and, ROS histochemical staining along with the NADPH oxidase activity were analyzed. Besides, photosynthetic pigments and damage to lipids and proteins were determined as oxidative stress indicators. Results showed that at 3 μM As, the cross-section areas of peanut roots were augmented; NADPH oxidase activity was significantly increased and O˙¯and HO accumulated in leaves and roots. Likewise, an increase in the lipid peroxidation and protein carbonyls was also observed throughout the plant regardless the inoculated strain, while chlorophylls and carotenes were increased only in those inoculated with Bradyrhizobium sp. C-145. Interestingly, the oxidative burst, mainly induced by the NADPH oxidase activity, and the consequent oxidative stress was strain-dependent and organ-differential. Additionally, As modifies the root anatomy, acting as a possibly first defense mechanism against the metalloid entry. All these findings allowed us to conclude that the redox response of peanut is conditioned by the rhizobial strain, which contributes to the importance of effectively formulating bioinoculants for this crop.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127410DOI Listing
November 2020

Genetic influence on cognitive development between childhood and adulthood.

Mol Psychiatry 2021 02 19;26(2):656-665. Epub 2018 Oct 19.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Successful cognitive development between childhood and adulthood has important consequences for future mental and physical wellbeing, as well as occupational and financial success. Therefore, delineating the genetic influences underlying changes in cognitive abilities during this developmental period will provide important insights into the biological mechanisms that govern both typical and atypical maturation. Using data from the Philadelphia Neurodevelopmental Cohort (PNC), a large population-based sample of individuals aged 8 to 21 years old (n = 6634), we used an empirical relatedness matrix to establish the heritability of general and specific cognitive functions and determine if genetic factors influence cognitive maturation (i.e., Gene × Age interactions) between childhood and early adulthood. We found that neurocognitive measures across childhood and early adulthood were significantly heritable. Moreover, genetic variance on general cognitive ability, or g, increased significantly between childhood and early adulthood. Finally, we did not find evidence for decay in genetic correlation on neurocognition throughout childhood and adulthood, suggesting that the same genetic factors underlie cognition at different ages throughout this developmental period. Establishing significant Gene × Age interactions in neurocognitive functions across childhood and early adulthood is a necessary first step in identifying genes that influence cognitive development, rather than genes that influence cognition per se. Moreover, since aberrant cognitive development confers risk for several psychiatric disorders, further examination of these Gene × Age interactions may provide important insights into their etiology.
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http://dx.doi.org/10.1038/s41380-018-0277-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570578PMC
February 2021

Rediscovering the value of families for psychiatric genetics research.

Mol Psychiatry 2019 04 28;24(4):523-535. Epub 2018 Jun 28.

South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas of the Rio Grande Valley, Brownsville, TX, USA.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.
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http://dx.doi.org/10.1038/s41380-018-0073-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028329PMC
April 2019

Finding potential cis-regulatory loci using allele-specific chromatin accessibility as weights in a kernel-based variance component test.

BMC Proc 2016 18;10(Suppl 7):103-108. Epub 2016 Oct 18.

South Texas Diabetes and Obesity Institute, University of Texas at the Rio Grande Valley, One West University Blvd., Brownsville, TX 78520 USA ; South Texas Diabetes and Obesity Institute, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229 USA.

We present a novel approach to detect potential -acting regulatory loci that combines the functional potential, an empirical DNase-seq based estimate of the allele-specificity of DNase-I hypersensitivity sites, with kernel-based variance component association analyses against expression phenotypes. To test our method we used public ENCODE whole genome DNase-I sequencing data, from a single sample, to estimate the functional potentials of the subset of 10,552 noncoding heterozygous single-nucleotide polymorphisms (SNPs) that were also present in the Genetic Analysis Workshop 19 (GAW19) family-based data set. We then built two covariance kernels, one nonweighted and one weighted by the functional potentials, and conducted kernel-based variance component association analyses against the 20,527 transcript expression phenotypes in the GAW19 family-based data set. We found signals of potential -regulatory effects, that surpassed the Bonferroni significance threshold, for ten transcripts. Stepwise removal of the -located SNPs from the weighted kernel lead to the disappearance of the association signal from our top transcript hit. We found compelling evidence of allele-specific -regulation for four transcripts using both kernels, and our results agree with previous research that suggests the involvement of specific -located variants in the regulation of their neighboring gene.
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http://dx.doi.org/10.1186/s12919-016-0013-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133489PMC
October 2016

Lack of Association between Variants and Type 2 Diabetes in Mexican American Families.

J Diabetes Res 2016 8;2016:6463214. Epub 2016 Nov 8.

South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Brownsville, TX, USA.

encodes zinc transporter 8 which is involved in packaging and release of insulin. Evidence for the association of variants with type 2 diabetes (T2D) is inconclusive. We interrogated single nucleotide polymorphisms (SNPs) around for association with T2D in high-risk, pedigreed individuals from extended Mexican American families. This study of 118 SNPs within 50 kb of the locus tested the association with eight T2D-related traits at four levels: (i) each SNP using measured genotype approach (MGA); (ii) interaction of SNPs with age and sex; (iii) combinations of SNPs using Bayesian Quantitative Trait Nucleotide (BQTN) analyses; and (iv) entire gene locus using the gene burden test. Only one SNP (rs7817754) was significantly associated with incident T2D but a summary statistic based on all T2D-related traits identified 11 novel SNPs. Three SNPs and one SNP were weakly but interactively associated with age and sex, respectively. BQTN analyses could not demonstrate any informative combination of SNPs over MGA. Lastly, gene burden test results showed that at best the locus could account for only 1-2% of the variability in T2D-related traits. Our results indicate a lack of association of the SNPs with T2D in Mexican American families.
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http://dx.doi.org/10.1155/2016/6463214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118530PMC
June 2017

Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families.

J Lipid Res 2014 May 13;55(5):939-46. Epub 2014 Mar 13.

Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227.

Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS.
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http://dx.doi.org/10.1194/jlr.M044065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995471PMC
May 2014

Genetic Analysis Workshop 17 mini-exome simulation.

BMC Proc 2011 Nov 29;5 Suppl 9:S2. Epub 2011 Nov 29.

Department of Genetics, Texas Biomedical Research Institute, 7620 NW Loop 410, San Antonio, TX 78245, USA.

The data set simulated for Genetic Analysis Workshop 17 was designed to mimic a subset of data that might be produced in a full exome screen for a complex disorder and related risk factors in order to permit workshop participants to investigate issues of study design and statistical genetic analysis. Real sequence data from the 1000 Genomes Project formed the basis for simulating a common disease trait with a prevalence of 30% and three related quantitative risk factors in a sample of 697 unrelated individuals and a second sample of 697 individuals in large, extended pedigrees. Called genotypes for 24,487 autosomal markers assigned to 3,205 genes and simulated affection status, quantitative traits, age, sex, pedigree relationships, and cigarette smoking were provided to workshop participants. The simulating model included both common and rare variants with minor allele frequencies ranging from 0.07% to 25.8% and a wide range of effect sizes for these variants. Genotype-smoking interaction effects were included for variants in one gene. Functional variants were concentrated in genes selected from specific biological pathways and were selected on the basis of the predicted deleteriousness of the coding change. For each sample, unrelated individuals and family, 200 replicates of the phenotypes were simulated.
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http://dx.doi.org/10.1186/1753-6561-5-S9-S2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287854PMC
November 2011

Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families.

Arch Gen Psychiatry 2010 Feb;67(2):168-77

Olin Neuropsychiatry Research Center, Whitehall Research Building, Institute of Living, Hartford, CT 06106, USA.

Context: Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes.

Objective: To adjudicate neurocognitive endophenotypes for bipolar disorder.

Design: All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status.

Setting: Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas.

Participants: Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia.

Main Outcome Measure: Neurocognitive test performance.

Results: Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory.

Conclusion: This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.
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http://dx.doi.org/10.1001/archgenpsychiatry.2009.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401550PMC
February 2010

A schizophrenia gene locus on chromosome 17q21 in a new set of families of Mexican and central american ancestry: evidence from the NIMH Genetics of schizophrenia in latino populations study.

Am J Psychiatry 2009 Apr 2;166(4):442-9. Epub 2009 Feb 2.

Psychiatric Genetics Center, University of Texas Health Science Center at San Antonio, Suite 200, 454 Soledad St., San Antonio, TX 78205, USA.

Objective: The present study investigated a new set of families of Latin American ancestry in order to detect the location of genes predisposing to schizophrenia and related psychotic disorders.

Method: A genome-wide scan was performed for 175 newly recruited families with at least two siblings suffering from a psychotic disorder. Best-estimate consensus procedures were used to arrive at diagnoses, and nonparametric allele-sharing statistics were calculated to detect linkage.

Results: Genome-wide significant evidence for linkage for the phenotype of DSM-IV schizophrenia or schizoaffective disorder was found in a region on chromosome 17q21 (lod score, 3.33). A region on chromosome 15q22-23 showed suggestive evidence of linkage with this same phenotype (lod score, 2.11). Analyses using a broader model (any psychosis) yielded evidence of suggestive linkage for the 17q21 region only, and no region achieved genome-wide significance of linkage.

Conclusions: The new set of 175 families of Mexican and Central American ancestry delineates two new loci likely to harbor predisposition genes for schizophrenia and schizoaffective disorder. The region with the strongest support for linkage in this sample, 17q21, has been implicated in meta-analyses of schizophrenia genome screens, but the authors found no previous reports of it as a locus for schizophrenia in specific population- or family-based studies, and it may represent the location of a schizophrenia predisposition gene (or genes) of special relevance in Mexican and Central American populations.
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http://dx.doi.org/10.1176/appi.ajp.2008.08040612DOI Listing
April 2009

A genome screen for quantitative trait loci influencing schizophrenia and neurocognitive phenotypes.

Am J Psychiatry 2008 Sep 15;165(9):1185-92. Epub 2008 Jul 15.

Department of Genetics, Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78249-0549, USA.

Objective: Deficits in neurocognitive function have been demonstrated in individuals with schizophrenia and in the unaffected family members of these individuals. Genetic studies of such complementary traits, along with traditional analyses of diagnosis, may help to elucidate the biological pathways underlying familial liability to schizophrenia and related disorders. The authors conducted a multiplex, multigenerational family study using a genome-wide screen for schizophrenia and related neurocognitive phenotypes.

Method: Participants were 1) 676 European American individuals from 43 families, ascertained through an individual with schizophrenia, and 2) 236 healthy comparison subjects. Participants were evaluated clinically and examined through the use of a computerized neurocognitive test battery that provided measures of accuracy and speed on the cognitive domains of abstraction and mental flexibility; attention; verbal, face, and spatial memory; language and reasoning; spatial and emotion processing; and sensorimotor dexterity. A genome-wide linkage screen was also performed. Healthy comparison subjects were included in order to obtain normative phenotypic data but were not genotyped.

Results: Significant evidence for linkage of schizophrenia to chromosome 19q was observed. Analysis of cognitive traits revealed significant linkage to chromosome 5q for the domains of abstraction and mental flexibility. A variety of other neurocognitive traits also showed nominal evidence of linkage to the 5q region. Joint analyses with diagnosis suggested that this quantitative trait locus may also influence schizophrenia.

Conclusions: Although chromosome 5 has been implicated in previous linkage studies of schizophrenia, the identification of the chromosome 19 quantitative trait locus is a novel finding. The identification of the chromosome 5 quantitative trait locus through linkage to neurocognitive phenotypes in the present study may inform functional hypotheses pertaining to how genotypes are connected to disease.
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http://dx.doi.org/10.1176/appi.ajp.2008.07121869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644284PMC
September 2008

Comparison of strategies for identification of regulatory quantitative trait loci of transcript expression traits.

BMC Proc 2007 18;1 Suppl 1:S85. Epub 2007 Dec 18.

Department of Epidemiology, University of North Carolina Chapel Hill, Bank of America Center, 137 East Franklin Street, Suite 306, CB #8050, Chapel Hill, North Carolina 27514, USA.

In order to identify regulatory genes, we determined the heritability of gene transcripts, performed linkage analysis to identify quantitative trait loci (QTLs), and evaluated the evidence for shared genetic effects among transcripts with co-localized QTLs in non-diseased participants from 14 CEPH (Centre d'Etude du Polymorphisme Humain) Utah families. Seventy-six percent of transcripts had a significant heritability and 54% of them had LOD score >or= 1.8. Bivariate genetic analysis of 15 transcripts that had co-localized QTLs on 4q28.2-q31.1 identified significant genetic correlation among some transcripts although no improvement in the magnitude of LOD scores in this region was noted. Similar results were found in analysis of 12 transcripts, that had co-localized QTLs in the 13q34 region. Principal-component analyses did not improve the ability to identify chromosomal regions of co-localized gene expressions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367462PMC
http://dx.doi.org/10.1186/1753-6561-1-s1-s85DOI Listing
December 2009

Effects on linkage analyses of different Affymetrix expression measures as quantitative trait phenotypes.

BMC Proc 2007 18;1 Suppl 1:S158. Epub 2007 Dec 18.

Centro de Investigación en Biología Celular y Molecular, Universidad de Costa Rica, Ciudad Universitaria Rodrigo Facio, 2060, San José, Costa Rica.

We compared results from linkage analyses of different phenotype measurements from the same gene expression traits and found that the strongest signals were detected by all expression measures that we considered. On average, that meant that the same quantitative trait loci (QTLs) were detected across methods, but the magnitude of the LOD score of each particular QTL and the false-positive ratio of QTL detection varied between the methods.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367575PMC
http://dx.doi.org/10.1186/1753-6561-1-s1-s158DOI Listing
December 2009

Adjudicating neurocognitive endophenotypes for schizophrenia.

Am J Med Genet B Neuropsychiatr Genet 2007 Mar;144B(2):242-9

Department of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, Texas 78229-3900, USA.

Although genetic influences on schizophrenia are well established, localization of the genes responsible for this illness has proven extremely difficult. Given evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, efforts have focused on developing endophenotypes. While several neuropsychological measures have been proposed to be endophenotypes, few studies have systematically assessed batteries of neurocognitive tests to determine which tests are most sensitive to liability for the illness. Two hundred sixty-nine Latino individuals were administered a standard neuropsychological battery. Two hundred fourteen of these were members of families with at least two siblings diagnosed with schizophrenia or schizoaffective disorder. The remaining were community controls without history of major psychiatric illness. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests covary with the degree of genetic relationship to affected individuals. Although five measures were found to uniquely model genetic liability for schizophrenia, digit symbol coding was the most sensitive. To assess the specificity of these endophenotypes, performance on these measures were compared to family members with bipolar and unipolar affective disorders. These markers clearly distinguished between individuals with psychotic illnesses and those with major depression. As measures contributed uniquely to discriminate individuals at varying risk for schizophrenia, our findings imply multiple independently inherited elements to the liability for the illness. We present a practical model for adjudicating endophenotypes and determining which measures are best suited for use in linkage analyses.
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http://dx.doi.org/10.1002/ajmg.b.30446DOI Listing
March 2007

Linkage disequilibrium across two different single-nucleotide polymorphism genome scans.

BMC Genet 2005 Dec 30;6 Suppl 1:S86. Epub 2005 Dec 30.

Centro de Investigación en Biología Celular y Molecular, Ciudad de la Investigación, Universidad de Costa Rica, San José, Costa Rica.

Linkage disequilibrium (LD) content was calculated for the Genetic Analysis Workshop 14 Affymetrix and Illumina single-nucleotide polymorphism (SNP) genome scans of the Collaborative Study on the Genetics of Alcoholism samples. Pair-wise LD was measured as both D' and r2 on 505 pedigree founder individuals. The r2 estimates were then used to correct the multipoint identity by descent matrix (MIBD) calculation to account for LD and LOD scores on chromosomes 3 and 18 were calculated for COGA's ttdt3 electrophysiological trait using those MIBDs. Extensive LD was observed throughout both marker sets, and it was higher in Affymetrix's more dense SNP map. However, SNP density did not solely account for Affymetrix's higher LD. MIBD estimation procedures assume linkage equilibrium to construct genotypes of non-genotyped pedigree founder individuals, and dense SNP genotyping maps are likely to contain moderate to high LD between markers. LOD score plots calculated after correction for LD followed the same general pattern as uncorrected ones. Since in our study almost half of the pedigree founders were genotyped, it is possible that LD had a minor impact on the LOD scores. Caution should probably be taken when using high density SNP maps when many non-genotyped founders are present in the study pedigrees.
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http://dx.doi.org/10.1186/1471-2156-6-S1-S86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866694PMC
December 2005
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