Karen Chorney

A Quantitative Trait Locus Associated With Cognitive Ability in Children

Quantitative trait loci (QTLs) associated with general cognitive ability (g) were investigated for several groups of children selected for very high or for average cognitive functioning. A DNA marker in the gene for insulin-like growth factor-2 receptor (IGF2R) on Chromosome 6 yielded a significantly greater frequency of a particular form of the gene (allele) in a high-g group (.303; average IQ = 136, N = 51) than in a control group (.156; average IQ = 103, N = 51). This association was replicated in an extremely-high-g group (all estimated IQs > 160, N = 52) as compared with an independent control group (average IQ = 101, N = 50), with allelic frequencies of .340 and .169, respectively. Moreover, a high-mathematics-ability group (N = 62) and a high-verbal-ability group (N = 51) yielded results that were in the same direction but only marginally significant (p = .06 and .08, respectively).

DNA markers associated with high versus low IQ: The IQ quantitative trait loci (QTL) project

General cognitive ability (intelligence, often indexed by IQ scores) is one of the most highly heritable behavioral dimensions. In an attempt to identify some of the many genes (quantitative trait loci; QTL) responsible for the substantial heritability of this quantitative trait, the IQ QTL Project uses an allelic association strategy. Allelic frequencies are compared for the high and low extremes of the IQ dimension using DNA markers in or near genes that are likely to be relevant to neural functioning. Permanent cell lines have been established for low-IQ (mean IQ=82;N=18), middle-IQ (mean IQ=105;N=21), and high-IQ (mean IQ=130;N=24) groups and for a replication sample consisting of even more extreme low-IQ (mean IQ=59;N=17) and high-IQ (mean IQ=142;N=27) groups. Subjects are Caucasian children tested from 6 to 12 years of age. This first report of the IQ QTL Project presents allelic association results for 46 two-allele markers and for 26 comparisons for 14 multiple-allele markers. Two markers yielded significant (p<.01) allelic frequency differences between the high- and the low-IQ groups in the combined sample—a new HLA marker for a gene unique to the human species and a new brain-expressed triplet repeat marker (CTGB33). The prospects for harnessing the power of molecular genetic techniques to identify QTL for quantitative dimensions of human behavior are discussed.

Allelic Associations between 100 DNA Markers and High versus Low IQ.

For DNA markers in or near genes of neurological relevance, allelic frequencies were compared for groups of White children high and low in IQ in an attempt to identify specific genes responsible for the substantial heritability of IQ scores. We previously reported results for 60 DNA markers and we now describe results for 40 additional markers. One sample consisted of high- and low-IQ groups with average IQs of 130 (N = 24) and 82 (N = 18), respectively. A replication sample was more extreme, including groups with average IQs of 142 (N = 27) and 59 (N = 17). Three of the 40 markers yielded significant allelic frequency differences between the high- and low-IQ groups in the original sample. In the replication sample, two of these markers (alcohol dehydrogenase 5 and the beta polypeptide of nerve growth factor) yielded results in the same direction but were not significant. The third marker (EST00083), derived from a cDNA hippocampal library, was also significant in the replication sample. As described in another article (Skuder et al., 1995) in this issue, this marker was found to involve mitochondrial DNA (mtDNA) rather than nuclear DNA. The unexpected nature of this marker suggests caution in claiming that the replicated association for EST00083 is indeed a quantitative trait loci (QTL) for IQ until the association receives additional support. This study provides statistical power to detect associations that account for about 2% of the IQ variance in the population. We are currently obtaining samples four times larger that will provide statistical power to detect allelic associations that account for considerably less than 1% of the variance.

Precise localisation of 3p25 breakpoints in four patients with the 3p-syndrome.

In patients with the 3p-syndrome, hemizygous deletion of 3p25-pter is associated with profound growth failure, characteristic facial features, and mental retardation. We performed a molecular genetic analysis of 3p25 breakpoints in four patients with the 3p- syndrome, and a fifth patient with a more complex abnormality, 46,XY,der(3)t(3;?)(p25.3;?). EBV transformed lymphoblasts from each of the patients were initially characterised using fluorescent in situ hybridisation (FISH) and polymorphic microsatellite analyses. The 3p-chromosome from each patient was isolated from the normal chromosome 3 in somatic cell hybrid lines and subsequently analysed with polymorphic and monomorphic PCR amplifiable markers from 3p25. The analysis clearly shows that all five breakpoints are distinct. Furthermore, we have identified yeast artificial chromosomes that cross the 3p25 breakpoints of all four 3p-patients. Two of the patients were deleted for the von Hippel-Lindau (VHL) tumour suppressor gene, although neither has yet developed evidence of VHL disease. The patient with the most centromeric breakpoint, between D3S1585 and D3S1263, had the most severe clinical phenotype including an endocardial cushion defect that was not observed in any of the four patients who had more telomeric breakpoints. This study should provide useful insights into critical regions within 3p25 that are involved in normal human growth and development.

γδ intraepithelial lymphocytes drive tumor necrosis factor-α responsiveness to intestinal iron challenge: relevance to hemochromatosis

Summary: The dependence of intestinal epithelial cell (IEC) growth and differentiation on intraepithelial lymphocytes (IELs) expressing the gamma/delta (γδ) T‐cell receptor (TCR), suggested a potential role for γδ+ IELs in the regulation of iron absorption. We therefore examined the levels of hepatic iron and the IEL cytokine responses in C57BL/6J control and class I and TCR knockout lines (placed on a C57BL/6J genetic background) following the administration of supplemental dietary iron. The highest level of liver iron was found in the β2‐microglobulin knockout (β2m‐/‐) mice followed by the TCR‐δ knockout (TCRδ‐/‐) animals. TCR‐α knockout (TCRα‐/‐) and control animals did not differ in their iron levels. Liver iron loading correlated inversely with rhe ability of the mice to generate an IEL tumor necrosis factor (TNE)‐α response. These observations suggest a model in which IEC iron loading is communicated to IELs via the HFE class I protein. The result of this communication is the initiation of TNE‐α release by γδ+ IELs (sustained by macrophages and dendritic cells) contributing to the upregulation of ferritin expression and possibly to the normal maintenance of the IEC apoptotic pathway.

NO ASSOCIATION BETWEEN GENERAL COGNITIVE ABILITY AND THE A1 ALLELE OF THE D2 DOPAMINE RECEPTOR GENE

Berman and Noble (1995) reported significantly reduced visuospatial performance in children with the TAQI A1 allele of the D2 dopamine receptor (DRD2) gene. Given that visuospatial performance loads highly on an unrotated principal component indexing general cognitive ability, we tested the association between DRJD2 and WISC-R IQ comparing 51 high-IQ, 51 average-IQ, and 35 low-IQ children in the IQ Quantitative Trait Loci (QTL) Project. No statistically significant association between the TAQI A DRD2 alleles and IQ was found. Given that a statistically significant portion of genetic variance for specific cognitive abilities is independent of general cognitive ability, it is possible that the TAQI DRD2 association is specific to visuospatial performance and independent of general cognitive ability.

DNA pooling and dense marker maps: a systematic search for genes for cognitive ability

Pooling DNA from subjects within a group and comparing the pooled DNA across groups for a dense map of DNA markers offers a solution to the conundrum that linkage is systematic but not powerful whereas allelic association is powerful but not systematic. We used DNA pooling to screen 66 markers on chromosome 22 in original and replication samples of children of high general cognitive ability (g) and controls of average g. Although none of these markers survived our three-stage screening design (original pooling, replication pooling, individual genotyping), the results of DNA pooling were largely confirmed by individual genotyping. We can therefore exclude associations of major effect size on chromosome 22 for g, a key variable for cognitive neuroscience research on learning and memory.

Dopamine markers and general cognitive ability

BECAUSE general cognitive ability (g) is among the most heritable behavioural traits, it is a reasonable target for a search for quantitative trait loci (QTLs). We used a selected-extremes design to test candidate genes for allelic association with g. Polymorphisms in four genes in the dopamine system (DRD2, DRD3, DRD4, DAT1) were genotyped for 51 high g children with IQ scores > 130 and for 51 average g control children. No significant allelic or genotypic differences were found between the high g and average g groups for these markers of the dopamine system, even though the selected-extremes design provides power to detect QTL associations that involve a relative risk of about 1.5.

A polymorphism in mitochondrial DNA associated with IQ

In an allelic association study of 100 DNA markers in or near genes of neurological relevance, one restriction fragment length polymorphism (RFLP) yielded significant differences between high- and low-IQ groups in two independent samples. The goal of this article is to describe how we tracked down the specific gene marked by the RFLP and to introduce some current techniques used to apply molecular genetics to complex traits like IQ. The RFLP, EST00083, is a brain-expressed sequence tag site (BESTS) derived from a cDNA hippocampal library. The cDNA clone was shown to involve a chimera between genomic DNA on Chromosome 6 and mitochondrial DNA (mtDNA). The RFLP was localized in the mtDNA rather than the genomic DNA. The RFLP is an MspI restriction site (CCGG) at 15,925 base pairs of the complete mitochondrial genome in a gene that codes for the transfer RNA for threonine. The mitochondrial origin of the EST00083 RFLP explains why the RFLP is maternally transmitted and never yields heterozygotes. Although mtDNA could be associated with IQ, such an unusual result requires further replication.

DNA markers associated with general and specific cognitive abilities

Abstract Multivariate quantitative genetic research suggests a hierarchical model of cognitive abilities where genetic effects are largely general, cutting across most cognitive abilities. Some genetic effects, however, are specific to certain cognitive abilities. These results lead to a hypothesis for molecular genetic research: Although most genes associated with one cognitive ability will be related to other cognitive abilities, some genes will be specific to a particular cognitive ability. The current research explored this hypothesis in an analysis of data in specific cognitive abilities from 86 children from 6 to 12 years of age from a larger allelic association study of general cognitive ability. Eight DNA markers were entered simultaneously in separate multiple regression analyses predicting each of four specific cognitive ability factors (Verbal, Spatial, Perceptual Speed, Memory), as well as WISC-R subtest scores. Four marjers (CTGB33, EST00083, HLA, and SOD2) showed similar effects across the cognitive ability scales, suggesting that they are related to general cognitive ability (g). These associations became negligible when the effects of ‘g’ (WISC-R IQ) were removed. Three markers (ADH5, DM, and NGFB) continued to be significantly associated with specific cognitive ability scales after the effects of ‘g’ were removed. Although preliminary, these molecular genetic results support the hierarchical model predicted by quantitative genetic research.