Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families - PubMed (original) (raw)

Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families

Maricela Alarcón et al. Am J Hum Genet. 2002 Jan.

Abstract

Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.

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Figures

Figure 1

Distributions of autism endophenotypes for each sex

Figure 2

Nonparametric QTL results of an autosomal genome scan for age at first word (solid line), age at first phrase (dotted line), and the composite measure of repetitive and stereotyped behavior (dashed line). Left, Chromosomes 1–12. Right, Chromosomes 13–22.

Figure 3

Nonparametric X-linkage results for WORD, PHRASE, and RSB for brother-brother (bold line), brother-sister (solid line), and sister-sister (dotted line) pairs.

Figure 4

Plots of nonparametric Z scores (calculated at 5-cM intervals) for WORD (solid line), PHRASE (dotted line), and RSB (dashed line) on chromosome 7. Previous loci identified for language deficits or autism are also included in the figure: the rectangle with diagonal stripes represents the region identified in a family with severe speech disorder (Fisher et al. 1998); the rectangle with cross-hatches represents the autism region reported in the initial IMGSAC (1998) study; and the arrow indicates the peak linkage result from an update of the IMGSAC study (IMGSAC 2001).

Figure 5

Plots of nonparametric Z scores for linkage analysis of 28 additional markers flanking the chromosome 7q region identified in the quantitative genome scan. Results for WORD (solid line), PHRASE (dotted line), and RSB (dashed line) are shown. The 10 markers included in the association analysis are listed in the figure. The rectangle with diagonal stripes represents the region identified in a family with severe speech disorder (Fisher et al. 1998); the rectangle with cross-hatches represents the autism region reported in the IMGSAC (1998) study; and the rectangle with dots represents the results of a linkage analysis using the narrow diagnosis of autism (Liu et al. 2001). The X-axis tick marks are at 2-cM intervals.