NTM and NR3C2 polymorphisms influencing intelligence: Family-based association studies

Department of Mathematics and Statistics, College of Arts and Sciences, East Tennessee State University, Johnson City, TN 37614, USA.
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 3.69). 10/2010; 35(1):154-60. DOI: 10.1016/j.pnpbp.2010.10.016
Source: PubMed


Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p<10(-3)) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p = 0.000764) and NR3C2 at 4q31.1 (rs3846329, p = 0.000675) were two novel genes which have not been associated with IQ in other studies. It has been reported that NTM might play a role in late-onset Alzheimer disease while NR3C2 may be associated with cognitive function and major depression. The associations of these two genes were well-replicated by single-marker and haplotype analyses in the IMAGE sample. In conclusion, our findings provide evidence that chromosome regions of 11q25 and 4q31.1 contain genes affecting IQ. This study will serve as a resource for replication in other populations.

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    • "Predominantly expressed in the brain, NTM promotes neurite outgrowth and adhesion via a homophilic mechanism [Sellar et al., 2003]. Interestingly , two genome wide association studies (GWAS) reported an association between NTM and cognitive function performances [Liu et al., 2007; Pan et al., 2011] and two studies have detected CNVs altering NTM in ASD and ID [Vorstman et al., 2006; Cooper et al., 2011]. "
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    ABSTRACT: Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Sep 2015 · American Journal of Medical Genetics Part A
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    • "treatment ( Garson , 2013 ; Ma et al . , 2012 ) . The autoregressive covariance structure was selected because the correlations between CSSA evaluations ( at times 1e4 ) declined with time . The IQ and skin color were tested as potential confounders . IQ was included since there are studies showing as - sociations of NR3C2 SNPs with intelligence ( Pan et al . , 2011 ; van der Voorn et al . , 2015 ) . As recommended in the literature , a variable is considered a confounder when it is associated with both variables of interest ( association with both the outcome and studied SNPs for a P - value < 0 . 2 ) ( Cordell , 2009 ; Maldonado and Greenland , 1993 ) ."
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    ABSTRACT: The aim of this study was to analyze hypotheses-driven gene-environment and gene-gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in mineralocorticoid and glucocorticoid receptor genes (NR3C2 and NR3C1, respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values ≤ 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Journal of Psychiatric Research
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    • "These include variants in the CHRM2, COMT and BDNF genes [14]. GWASs, which have recently had an enormous success in identifying genetic variants contributing to complex traits, had little success in mapping variants associated with cognitive abilities, with no indication of major genetic contributing loci [16], [22], [23]. The generally accepted model proposes that cognitive abilities are influenced by many genes of small effect [24] and are therefore difficult to map in the relatively small-sized samples currently available. "
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    ABSTRACT: Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.
    Full-text · Article · Nov 2012 · PLoS ONE
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