A genomewide screen of 345 families for autism-susceptibility loci

Abstract

We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20). In this follow-up analysis we have increased the sample size threefold, while holding the study design constant, so that we now report 345 multiplex families, each with at least two siblings affected with autism or ASD phenotype. Along with 235 new multiplex families, 73 new microsatellite markers were also added in 10 regions, thereby increasing the marker density at these strategic locations from 10 cM to approximately 2 cM and bringing the total number of markers to 408 over the entire genome. Multipoint maximum LOD scores (MLS) obtained from affected-sib-pair analysis of all 345 families yielded suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order by MLS) (P <.01). The most significant findings were an MLS of 2.83 (P =.00029) on chromosome 17q, near the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), and an MLS of 2.54 (P =.00059) on 5p. The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions.

Figure 1

Multipoint MLS results from Mapmaker/Sibs ASP analysis, shown by chromosome. The X-axis depicts genetic distance in Kosambi centimorgans from pter (zero coordinate) to qter; the Y-axis represents the MLS for all autosomes and the X-MLS for the X chromosome. Thin lines represent the narrow disease classification; thick lines represent the broad disease classification (see the “Families and Methods” section). Black bars below the X-axis show regions with dense microsatellite marker coverage.

Figure 1

Multipoint MLS results from Mapmaker/Sibs ASP analysis, shown by chromosome. The X-axis depicts genetic distance in Kosambi centimorgans from pter (zero coordinate) to qter; the Y-axis represents the MLS for all autosomes and the X-MLS for the X chromosome. Thin lines represent the narrow disease classification; thick lines represent the broad disease classification (see the “Families and Methods” section). Black bars below the X-axis show regions with dense microsatellite marker coverage.

Figure 2

Comparison of the three stages of ASP analysis for selected chromosomes. The X-axis depicts genetic distance in Kosambi centimorgans from pter (zero coordinate) to qter; the Y-axis represents the MLS for all autosomes and the X-MLS for the X chromosome. Thick red lines represent analysis of updated stage 1 (110 families) (see the “Families and Methods” section); hatched blue lines represent analysis of stage 2 (156 families); and black lines represent analysis of stage 3 (345 families).