Effects of Updating Linkage Evidence across Subsets of Data: Reanalysis of the Autism Genetic Resource Exchange Data Set
2005; Elsevier BV; Volume: 76; Issue: 4 Linguagem: Inglês
10.1086/429345
ISSN1537-6605
AutoresChristopher W. Bartlett, Rhinda Goedken, Veronica J. Vieland,
Tópico(s)Virology and Viral Diseases
ResumoResults of autism linkage studies have been difficult to interpret across research groups, prompting the use of ever-increasing sample sizes to increase power. However, increasing sample size by pooling disparate collections for a single analysis may, in fact, not increase power in the face of genetic heterogeneity. Here, we applied the posterior probability of linkage (PPL), a method designed specifically to analyze multiple heterogeneous data sets, to the Autism Genetic Resource Exchange collection of families by analyzing six clinically defined subsets of the data and updating the PPL sequentially over the subsets. Our results indicate a substantial probability of linkage to chromosome 1, which had been previously overlooked; our findings also provide a further characterization of the possible parent-of-origin effects at the 17q11 locus that were previously described in this sample. This analysis illustrates that the way in which heterogeneity is addressed in linkage analysis can dramatically affect the overall conclusions of a linkage study. Results of autism linkage studies have been difficult to interpret across research groups, prompting the use of ever-increasing sample sizes to increase power. However, increasing sample size by pooling disparate collections for a single analysis may, in fact, not increase power in the face of genetic heterogeneity. Here, we applied the posterior probability of linkage (PPL), a method designed specifically to analyze multiple heterogeneous data sets, to the Autism Genetic Resource Exchange collection of families by analyzing six clinically defined subsets of the data and updating the PPL sequentially over the subsets. Our results indicate a substantial probability of linkage to chromosome 1, which had been previously overlooked; our findings also provide a further characterization of the possible parent-of-origin effects at the 17q11 locus that were previously described in this sample. This analysis illustrates that the way in which heterogeneity is addressed in linkage analysis can dramatically affect the overall conclusions of a linkage study. Autism spectrum disorder (ASD [MIM 209850]) is a relatively rare pervasive developmental disorder that presents with abnormal development of language and social responses/initiation and is also characterized by stereotypic behavioral repertoires (Fombonne Fombonne, 1999Fombonne E The epidemiology of autism: a review.Psychol Med. 1999; 29: 769-786Crossref PubMed Scopus (653) Google Scholar; Folstein and Rosen-Sheidley Folstein and Rosen-Sheidley, 2001Folstein SE Rosen-Sheidley B Genetics of autism: complex aetiology for a heterogeneous disorder.Nat Rev Genet. 2001; 2: 943-955Crossref PubMed Scopus (623) Google Scholar). Autism is presumed to have a genetic basis—as suggested, for example, by twin studies—and numerous groups have undertaken the search for susceptibility genes (International Molecular Genetic Study of Autism Consortium International Molecular Genetic Study of Autism Consortium, 1998International Molecular Genetic Study of Autism Consortium A full genome screen for autism with evidence for linkage to a region on chromosome 7q.Hum Mol Genet. 1998; 7: 571-578Crossref PubMed Scopus (475) Google Scholar; Paris Autism Research International Sibpair Study Paris Autism Research International Sibpair Study, 1999Paris Autism Research International Sibpair Study Genome-wide scan for autism susceptibility genes.Hum Mol Genet. 1999; 8: 805-812Crossref PubMed Scopus (417) Google Scholar; Risch et al. 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Liu et al., 2001Liu J Nyholt DR Magnussen P Parano E Pavone P Geschwind D Lord C Iversen P Hoh J Autism Genetic Resource Exchange Ott J Gilliam TC A genomewide screen for autism susceptibility loci.Am J Hum Genet. 2001; 69: 327-340Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar; Alarcón et al. Alarcón et al., 2002Alarcón M Cantor RM Liu J Gilliam TC Autism Genetic Resource Exchange Consortium Geschwind DH Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.Am J Hum Genet. 2002; 70: 60-71Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar; Shao et al. Shao et al., 2002bShao Y Wolpert CM Raiford KL Menold MM Donnelly SL Ravan SA Bass MP McClain C von Wendt L Vance JM Abramson RH Wright HH Ashley-Koch A Gilbert JR DeLong RG Cuccaro ML Pericak-Vance MA Genomic screen and follow-up analysis for autistic disorder.Am J Med Genet. 2002b; 114: 99-105Crossref PubMed Scopus (198) Google Scholar; Yonan et al. Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). However, the results of these genome scans have not yielded consistent locations for autism susceptibility loci, with results typically shifting and becoming less clear as more families are added to each individual collection (Wassink et al. Wassink et al., 2004Wassink TH Brzustowicz LM Bartlett CW Szatmari P The search for autism genes.Ment Retard Dev Disabil Res Rev. 2004; 10: 272-283Crossref PubMed Scopus (79) Google Scholar). Across family collections, there has been some concordance for findings on 2q and 7q, but there is still no clear and convincing evidence of any specific linkage location. Locus heterogeneity may play a substantial role in the problems encountered in autism linkage studies. Strategies for mitigating the effects of locus heterogeneity include the use of phenotypic characteristics to define more homogeneous subsets of the data and the use of statistical techniques that specifically allow for subgroup differences. Many groups have tried subsetting their family collections on the basis of phenotypic characteristics derived from the Autism Diagnostic Interview–Revised (ADI-R) (Lord et al. Lord et al., 1994Lord C Rutter M Le Couteur A Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.J Autism Dev Disord. 1994; 24: 659-685Crossref PubMed Scopus (6281) Google Scholar), such as delay in acquisition of phrase speech (Bradford et al. Bradford et al., 2001Bradford Y Haines J Hutcheson H Gardiner M Braun T Sheffield V Cassavant T Huang W Wang K Vieland V Folstein S Santangelo S Piven J Incorporating language phenotypes strengthens evidence of linkage to autism.Am J Med Genet. 2001; 105: 539-547Crossref PubMed Scopus (118) Google Scholar; Buxbaum et al. Buxbaum et al., 2001Buxbaum JD Silverman JM Smith CJ Kilifarski M Reichert J Hollander E Lawlor BA Fitzgerald M Greenberg DA Davis KL Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.Am J Hum Genet. 2001; 68 (erratum 69:470): 1514-1520Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar; Shao et al. Shao et al., 2002aShao Y Raiford KL Wolpert CM Cope HA Ravan SA Ashley-Koch AA Abramson RK Wright HH DeLong RG Gilbert JR Cuccaro ML Pericak-Vance MA Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder.Am J Hum Genet. 2002a; 70: 1058-1061Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar) or other traits (Nurmi et al. Nurmi et al., 2003Nurmi EL Dowd M Tadevosyan-Leyfer O Haines JL Folstein SE Sutcliffe JS Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13.J Am Acad Child Adolesc Psychiatry. 2003; 42: 856-863Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar; Shao et al. Shao et al., 2003Shao Y Cuccaro ML Hauser ER Raiford KL Menold MM Wolpert CM Ravan SA Elston L Decena K Donnelly SL Abramson RK Wright HH DeLong GR Gilbert JR Pericak-Vance MA Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes.Am J Hum Genet. 2003; 72: 539-548Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar), as well as, more recently, sex of the affected pairs (Stone et al. Stone et al., 2004Stone JL Merriman B Cantor RM Yonan AL Gilliam TC Geschwind DH Nelson SF Evidence for sex-specific risk alleles in autism spectrum disorder.Am J Hum Genet. 2004; 75: 1117-1123Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Here, we reanalyze the data presented by Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar), which are in the public domain as part of the Autism Genetic Resource Exchange (AGRE) (Geschwind et al. Geschwind et al., 2001Geschwind DH Sowinski J Lord C Iversen P Shestack J Jones P Ducat L Spence SJ The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions.Am J Hum Genet. 2001; 69: 463-466Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). We compare the original results of Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar) with what we obtain using an alternative data-analysis method that has been specifically designed to allow for heterogeneity within the sample, and we find that the results of a genome screen can be highly dependent upon the choice of data-analysis method in the (presumed) presence of locus heterogeneity. The data used in our analyses comprise a subset of the AGRE families included by Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar); some of these families have been included in additional publications as well (Liu et al. Liu et al., 2001Liu J Nyholt DR Magnussen P Parano E Pavone P Geschwind D Lord C Iversen P Hoh J Autism Genetic Resource Exchange Ott J Gilliam TC A genomewide screen for autism susceptibility loci.Am J Hum Genet. 2001; 69: 327-340Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar; Alarcón et al. Alarcón et al., 2002Alarcón M Cantor RM Liu J Gilliam TC Autism Genetic Resource Exchange Consortium Geschwind DH Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.Am J Hum Genet. 2002; 70: 60-71Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar; Yonan et al. Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar; Stone et al. Stone et al., 2004Stone JL Merriman B Cantor RM Yonan AL Gilliam TC Geschwind DH Nelson SF Evidence for sex-specific risk alleles in autism spectrum disorder.Am J Hum Genet. 2004; 75: 1117-1123Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Briefly, the sample consists of 303 multiplex families—primarily, affected sib pairs with genotyped parents—in which the children were ascertained for ASDs, including autism, Asperger syndrome, and pervasive developmental disorder (PDD). Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar) used 345 families. Of these, 11 families tested positive for fragile X syndrome in March 2004, subsequent to the publication of the study by Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar), and are omitted from our analyses; in addition, 31 families were trios with no linkage information and have also been omitted here. (Thus, the actual difference between the sample used by Yonan et al. [Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar] and the one used in our study should be just the 11 families with fragile X syndrome that were included in their study but omitted in ours.) ADI-R data were available for all affected subjects (Lord et al. Lord et al., 1994Lord C Rutter M Le Couteur A Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.J Autism Dev Disord. 1994; 24: 659-685Crossref PubMed Scopus (6281) Google Scholar). We used all of the genotypes from AGRE that were publicly available at the time of analysis: the 408 microsatellites reported by Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar), including markers at ∼10-cM resolution from the Marshfield genome screening set, version 8 (see the Center for Medical Genetics Web site), as well as 73 additional markers that were used to follow up on results from previous analyses of these data (Liu et al. Liu et al., 2001Liu J Nyholt DR Magnussen P Parano E Pavone P Geschwind D Lord C Iversen P Hoh J Autism Genetic Resource Exchange Ott J Gilliam TC A genomewide screen for autism susceptibility loci.Am J Hum Genet. 2001; 69: 327-340Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar; Alarcón et al. Alarcón et al., 2002Alarcón M Cantor RM Liu J Gilliam TC Autism Genetic Resource Exchange Consortium Geschwind DH Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.Am J Hum Genet. 2002; 70: 60-71Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar; Yonan et al. Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). Genotypic data were read into our Oracle database from J. A. Badner’s “hypercleaned” data file, which is available on the AGRE Web site. Any discrepancies between the diagnosis in Badner’s file and the AGRE diagnosis were resolved by substituting the AGRE diagnosis. Allele frequencies were estimated by allele counting in all founders. Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar) analyzed these data as a single group—that is, without explicitly considering possible group differences. They used the multipoint maximum LOD score (MLS) (Risch Risch, 1990Risch N Linkage strategies for genetically complex traits. II. The power of affected relative pairs.Am J Hum Genet. 1990; 46: 229-241PubMed Google Scholar) to analyze the data and an approximate “model-free” LOD (Göring and Terwilliger Göring and Terwilliger, 2000Göring HH Terwilliger JD Linkage analysis in the presence of errors IV: joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified.Am J Hum Genet. 2000; 66: 1310-1327Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar) for two-point analysis. They found their maximum MLS at position 17q11 (MLS=2.83) and identified other “suggestive” MLSs on chromosomes 5, 11, 4, and 8 (MLSs of 2.54, 2.24, 1.72, and 1.60, respectively). (Although there may be other small discrepancies between Badner’s files and the data used in the original report by Yonan et al. [Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar], we have verified that Badner's files produce essentially the same MLS results, with a maximum MLS of 2.7 on 17q11; in addition, the rank order of these other signals was unchanged, with the exception that the chromosome 5 MLS is only 1.7 and drops in rank from number 2 to number 4.) For our reanalysis of these data, we divided the sample into six subsets, which are defined a priori as follows: if at least two siblings met the International Classification of Disease 10 (ICD-10) algorithm for autism, we assigned the family to class I; if only one child met criteria for ICD-10 autism (and at least one additional child met criteria for Asperger syndrome or PDD), we assigned the family to class II. The remaining families, which contained no cases of ICD-10 autism (but at least two cases of Asperger syndrome or PDD), were assigned to class III. The rationale for this division was to achieve greater clinical homogeneity within subgroups. Each of these classes was further broken down on the basis of whether or not at least two affected siblings (with autism, Asperger syndrome, or PDD) presented with a phrase speech delay (PSD) of >36 mo (groups with at least two affected siblings with a PSD of >36 mo are referred to as “PSD positive”; groups without at least two affected siblings with a PSD of >36 mo are referred to as “PSD negative”). This division was based on previous findings from independent groups supporting likely genetic differences between families with and without multiplex PSD (Bradford et al. Bradford et al., 2001Bradford Y Haines J Hutcheson H Gardiner M Braun T Sheffield V Cassavant T Huang W Wang K Vieland V Folstein S Santangelo S Piven J Incorporating language phenotypes strengthens evidence of linkage to autism.Am J Med Genet. 2001; 105: 539-547Crossref PubMed Scopus (118) Google Scholar; Buxbaum et al. Buxbaum et al., 2001Buxbaum JD Silverman JM Smith CJ Kilifarski M Reichert J Hollander E Lawlor BA Fitzgerald M Greenberg DA Davis KL Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.Am J Hum Genet. 2001; 68 (erratum 69:470): 1514-1520Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar; Shao et al. Shao et al., 2002aShao Y Raiford KL Wolpert CM Cope HA Ravan SA Ashley-Koch AA Abramson RK Wright HH DeLong RG Gilbert JR Cuccaro ML Pericak-Vance MA Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder.Am J Hum Genet. 2002a; 70: 1058-1061Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar; Vieland et al. Vieland et al., 2003Vieland VJ Sheffield V Wassink T Beck J Goedken R Childress D Piven J A new genome screen for autism based on the posterior probability of linkage and incorporating language-based phenotypes finds evidence of linkage to several genomic locations, each supported by independent sources of information.Am J Hum Genet Suppl. 2003; 73: 174Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). Note that all of the families we included were also included in the Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar) analysis. We did not add or drop families on the basis of clinical status; we merely classified them with respect to clinical status in the analyses. Table 1 shows the sample-size breakdown of the AGRE families by subset. A complete list (by subset) of the families used in our analysis is available in appendix a (online only).Table 1Number of Families, by SubsetNo. of Families in SubsetClassPSD PositivePSD NegativeTotal No. of FamiliesI13365198II514596III549 Total189114303 Open table in a new tab We then analyzed the data by use of the posterior probability of linkage (PPL), which is specifically designed to allow for differences between subgroups (Vieland Vieland, 1998Vieland VJ Bayesian linkage analysis, or: how I learned to stop worrying and love the posterior probability of linkage.Am J Hum Genet. 1998; 63: 947-954Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). The PPL is parameterized in terms of an approximating single-locus model, allowing for heterogeneity under the admixture model (Smith Smith, 1963Smith CAB Testing for heterogeneity of recombination fraction values in human genetics.Ann Hum Genet. 1963; 27: 175-182Crossref PubMed Scopus (219) Google Scholar). All parameters of this model (gene frequency, three penetrances, and the admixture parameter) are integrated out of the likelihood, independently for each subset, and the resulting marginal posterior density in the recombination fraction (two-point) or genomic location (multipoint) is sequentially updated across the subsets (Vieland et al. Vieland et al., 2001Vieland VJ Wang K Huang J Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-based linkage methods for affected sib pair data.Hum Hered. 2001; 51: 199-208Crossref PubMed Scopus (52) Google Scholar; Vieland and Logue Vieland and Logue, 2002Vieland VJ Logue M HLODs, trait models, and ascertainment: implications of admixture for parameter estimation and linkage detection.Hum Hered. 2002; 53: 23-35Crossref PubMed Scopus (32) Google Scholar; Logue et al. Logue et al., 2003Logue MW Vieland VJ Goedken RJ Crowe RR Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7.Am J Med Genet B Neuropsychiatr Genet. 2003; 121: 95-99Crossref Scopus (45) Google Scholar; Logue and Vieland Logue and Vieland, 2004Logue MW Vieland VJ A new method for computing the multipoint posterior probability of linkage.Hum Hered. 2004; 57: 90-99Crossref PubMed Scopus (18) Google Scholar). In this way, the PPL allows for heterogeneity within subsets, as well as for differences across subsets, while accumulating the total evidence for and against linkage based on all families in a mathematically rigorous way. Because the PPL does not involve maximum-likelihood estimation or maximization of linkage statistics across subsets, there is no inflation of the PPL inherent in either updating across data subsets or subsetting on the basis of genetically irrelevant factors (see table 3 for an illustration). However, we have shown that, in the presence of heterogeneity within and across subsets, sequential updating across relevant clinical features can improve ability to find linkage (Wang et al. Wang et al., 1999Wang K Vieland VJ Huang J A Bayesian approach to replication of linkage studies.Genet Epidemiol. 1999; 17: S749-S754Crossref PubMed Scopus (24) Google Scholar; Huang and Vieland Huang and Vieland, 2001Huang J Vieland VJ Comparison of “model-free” and “model-based” linkage statistics in the presence of locus heterogeneity: single data set and multiple data set applications.Hum Hered. 2001; 51: 217-225Crossref PubMed Scopus (35) Google Scholar; Vieland et al. Vieland et al., 2001Vieland VJ Wang K Huang J Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-based linkage methods for affected sib pair data.Hum Hered. 2001; 51: 199-208Crossref PubMed Scopus (52) Google Scholar; Bartlett et al. Bartlett et al., 2002Bartlett CW Flax JF Logue MW Vieland VJ Bassett AS Tallal P Brzustowicz LM A major susceptibility locus for specific language impairment is located on 13q21.Am J Hum Genet. 2002; 71: 45-55Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, Bartlett et al., 2004Bartlett CW Flax JF Logue MW Smith BJ Vieland VJ Tallal P Brzustowicz LM Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment.Hum Hered. 2004; 57: 10-20Crossref PubMed Scopus (78) Google Scholar; Logue et al. Logue et al., 2003Logue MW Vieland VJ Goedken RJ Crowe RR Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7.Am J Med Genet B Neuropsychiatr Genet. 2003; 121: 95-99Crossref Scopus (45) Google Scholar). The PPL is on the probability scale, with values >2% (the prior probability of linkage) indicating evidence in favor of linkage and values <2% indicating evidence against linkage.Table 3Permutation Results at Linked and Unlinked LociPPL (%) forLocusRandom Subsets [SD]Pooled Data1q23-242.1 [2.8]1.7Unlinked.3 [.4]1.2Note.—Families were randomly permuted into six subsets, corresponding to the observed clinical subset sizes, and the PPL was sequentially updated across these random subsets. One thousand permutations were performed at each locus, and the average (SD) was calculated across permutations. PPLs for pooled data, shown for comparison, were computed by treating all six subsets as a single data set (i.e., without sequential updating across subgroups). Open table in a new tab Note.— Families were randomly permuted into six subsets, corresponding to the observed clinical subset sizes, and the PPL was sequentially updated across these random subsets. One thousand permutations were performed at each locus, and the average (SD) was calculated across permutations. PPLs for pooled data, shown for comparison, were computed by treating all six subsets as a single data set (i.e., without sequential updating across subgroups). Figure 1 shows multipoint PPLs across the genome. Overall, 83% of the genome yielded PPLs <2%; interestingly, this includes most of chromosome 7 (72%), with the 7q34-qter interval being the largest contiguous region with PPLs not <2%. The largest PPL is 55%, located at 1q23-24. Table 2 compares our results with the MLS and LOD results of Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar), in order of decreasing PPL. We note that the rank order of scores differs between the PPL and both the MLS and the LOD analyses.Table 2Results of Present Analysis, Compared with Those of Yonan et al. (Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar)Multipoint AnalysisTwo-Point AnalysisPPLYonan et al. Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google ScholarPPLYonan et al. Yonan et al., 2003Yonan AL Alarcón M Cheng R Magnusson PK Spence SJ Palmer AA Grunn A Juo SH Terwilliger JD Liu J Cantor RM Geschwind DH Gilliam TC A genomewide screen of 345 families for autism-susceptibility loci.Am J Hum Genet. 2003; 73: 886-897Abstract Full Text Full Text PDF PubMed Scopus (224) Google ScholarChromosome%Position (cM)MLSPositi
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