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Biomedical subjects

John C DeFries

Publications and source records attributed to John C DeFries.

6 recordsLinked to original sources
PubMed2002

Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder.

Comorbidity is pervasive among both adult and child psychiatric disorders; however, the etiological mechanisms underlying the majority of comorbidities are unknown. This study used genetic linkage analysis to assess the etiology of comorbidity between reading disability (RD) and attention-deficit hyperactivity disorder (ADHD), two common childhood disorders that frequently co-occur. Sibling pairs (N = 85) were ascertained initially because at least one individual in each pair exhibited a history of reading difficulties. Univariate linkage analyses in sibling pairs selected for ADHD from within this RD-ascertained sample suggested that a quantitative trait locus (QTL) on chromosome 6p is a susceptibility locus for ADHD. Because this QTL is in the same region as a well-replicated QTL for reading disability, subsequent bivariate analyses were conducted to test if this QTL contributed to comorbidity between the two disorders. Analyses of data from sib pairs selected for reading deficits revealed suggestive bivariate linkage for ADHD and three measures of reading difficulty, indicating that comorbidity between RD and ADHD may be due at least in part to pleiotropic effects of a QTL on chromosome 6p.

Analysis of Variance↗
PubMed2002

Dopamine transporter polymorphism associated with externalizing behavior problems in children.

Early childhood externalizing behavior is a stable and heritable pattern of aggressive and delinquent behavior that often leads to the development of serious psychiatric disorders such as conduct disorder and attention deficit hyperactivity disorder. We examined the relationship between parent reported externalizing behavior (assessed at ages 4, 7, and 9 years) and the VNTR polymorphism of the 3' untranslated region of SLC6A3 (DAT1) in a community sample of 790 children ascertained as part of our longitudinal twin and adoption studies. We applied the sibling-based methodology developed by Fulker et al. [1999: Am J Hum Genet 64:259-267] for estimating allelic association with quantitative traits, while controlling for population stratification. An extension of these methods allowed for the inclusion of monozygotic twins, dizygotic twins, siblings, and singletons. We have demonstrated that the 9-repeat variant of the DAT1 is a significant risk allele for externalizing behavior at ages 4 (P=0.001) and 7 years (P=0.02). Although the effect size was negligible at age 9 (P=0.92), a formal test of the developmental decrease in effect across the three ages was non-significant (P=0.70).

Adolescent↗
PubMed2002

Differential genetic etiology of reading component processes as a function of IQ.

Results obtained from previous studies of word recognition, reading component skills, and reading composite measures suggest that genetic factors may be more important as a cause for reading disability among children with higher IQ scores than among those with lower IQ scores. To investigate the genetic etiology of reading disability further, measures of word recognition, phonological decoding, orthographic coding, and phoneme awareness were obtained from a total of 465 twin pairs with a positive school history of reading problems. The basic and extended DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data were employed to investigate the etiology of group deficits in reading and language skills, as well as to assess differential genetic etiology for the reading-related measures as a function of IQ. Data from 168 sibling pairs (drawn from the twins' families), including fraternal twin pairs and their siblings, as well as non-twin siblings of identical twins were subjected to single-marker analyses using the DF basic linkage model to examine evidence for linkage of a quantitative-trait locus (QTL) for reading and language deficits to the short arm of chromosome 6. Lastly, to investigate the possible differential influence of this QTL as a function of IQ, the sibling pair data were fitted to an extension of the DF basic linkage model. Results indicated that reading and language deficits are significantly heritable and that differential genetic influences as a function of IQ are evident for measures of word recognition and phonological decoding. Results obtained from linkage analyses confirmed the presence of a QTL on chromosome 6p that influences phonological and orthographic skills, as well as phoneme awareness measures, and suggest that this QTL may influence phoneme awareness differentially as a function of IQ: however, future analyses with considerably larger samples are needed to test the hypothesis of differential QTL influence more rigorously.

Adolescent↗
PubMed2002

Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1.

A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values<0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.

Chromosome Mapping↗
PubMed2001

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia.

Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.

Child↗