A major susceptibility locus for specific language impairment is located on 13q21

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.     

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person’s ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14–q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.     

Examination of potential overlap in autism and language loci on chromosomes 2, 7, and 13 in two independent samples ascertained for specific language impairment

Specific language impairment is a neurodevelopmental disorder characterized by impairments essentially restricted to the domain of language and language learning skills. This contrasts with autism, which is a pervasive developmental disorder defined by multiple impairments in language, social reciprocity, narrow interests and/or repetitive behaviors. Genetic linkage studies and family data suggest that the two disorders may have genetic components in common. Two samples, from Canada and the US, selected for specific language impairment were genotyped at loci where such common genes are likely to reside. Significant evidence for linkage was previously observed at chromosome 13q21 in our Canadian sample (HLOD 3.56) and was confirmed in our US sample (HLOD 2.61). Using the posterior probability of linkage (PPL) to combine evidence for linkage across the two samples yielded a PPL over 92%. Two additional loci on chromosome 2 and 7 showed weak evidence for linkage. However, a marker in the cystic fibrosis transmembrane conductance regulator (7q31) showed evidence for association to SLI, confirming results from another group (O'Brien et al. 2003). Our results indicate that using samples selected for components of the autism phenotype may be a useful adjunct to autism genetics.     

Association of D16S515 microsatellite with specific language impairment on Robinson Crusoe Island, an isolated Chilean population: a possible key to understanding language development

Specific language impairment (SLI) is a developmental language disorder that occurs for no known reason. The disorder affects 2-8% of children. Some scientific evidence suggests that genetic factors are implicated in the etiology of SLI. The disorder is genetically complex. Two novel loci, SLI1 on chromosome 16q24 (MIM 606711) and SLI2 on chromosome 19q13 (MIM 606712), have been found to be highly correlated with SLI. Four genes have been identified as susceptibility genes. SLI occurs at an unusually elevated incidence (35%) among the population of Robinson Crusoe Island (Chile), which also has a high consanguinity rate. This finding supports the influence of genetic mechanisms in the transmission of SLI based on a founder effect. To investigate further the genetic involvement in this population, we collected blood samples from 115 islanders from 13 families with a language-impaired proband and from 18 families with a normal-language proband. The analysis of micro satellite marker D16S515, located in locus SLI1, demonstrated that the 230-bp allele was correlated with SLI and that the 232-bp allele was correlated with normal language development. The domain containing the D16S515 marker, therefore, may play a role in language development.     

Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are 1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).     

Defining the genetic architecture of human developmental language impairment

Language is a uniquely human trait, which poses limitations on animal models for discovering biological substrates and pathways. Despite this challenge, rapidly developing biotechnology in the field of genomics has made human genetics studies a viable alternative route for defining the molecular neuroscience of human language. This is accomplished by studying families that transmit both normal and disordered language across generations. The language disorder reviewed here is specific language impairment (SLI), a developmental deficiency in language acquisition despite adequate opportunity, normal intelligence, and without any apparent neurological etiology. Here, we describe disease gene discovery paradigms as applied to SLI families and review the progress this field has made. After review the evidence that genetic factors influence SLI, we discuss methods and findings from scans of the human chromosomes, including the main replicated regions on chromosomes 13, 16 and 19 and two identified genes, ATP2C2 and CMIP that appear to account for the language variation on chromosome 16. Additional work has been done on candidate genes, i.e., genes chosen a priori and not through a genome scanning studies, including several studies of CNTNAP2 and some recent work implicating BDNF as a gene x gene interaction partner of genetic variation on chromosome 13 that influences language. These recent developments may allow for better use of post-mortem human brain samples functional studies and animal models for circumscribed language subcomponents. In the future, the identification of genetic variation associated with language phenotypes will provide the molecular pathways to understanding human language.     

Genetic and phenotypic effects of phonological short-term memory and grammatical morphology in specific language impairment

Deficits in phonological short-term memory and aspects of verb grammar morphology have been proposed as phenotypic markers of specific language impairment (SLI) with the suggestion that these traits are likely to be under different genetic influences. This investigation in 300 first-degree relatives of 93 probands with SLI examined familial aggregation and genetic linkage of two measures thought to index these two traits, non-word repetition and tense marking. In particular, the involvement of chromosomes 16q and 19q was examined as previous studies found these two regions to be related to SLI. Results showed a strong association between relatives' and probands' scores on non-word repetition. In contrast, no association was found for tense marking when examined as a continuous measure. However, significant familial aggregation was found when tense marking was treated as a binary measure with a cut-off point of −1.5 SD, suggestive of the possibility that qualitative distinctions in the trait may be familial while quantitative variability may be more a consequence of non-familial factors. Linkage analyses supported previous findings of the SLI Consortium of linkage to chromosome 16q for phonological short-term memory and to chromosome 19q for expressive language. In addition, we report new findings that relate to the past tense phenotype. For the continuous measure, linkage was found on both chromosomes, but evidence was stronger on chromosome 19. For the binary measure, linkage was observed on chromosome 19 but not on chromosome 16.     

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.     

Association of specific language impairment (SLI) to the region of 7q31

FOXP2 (forkhead box P2) was the first gene characterized in which a mutation affects human speech and language abilities. A common developmental language disorder, specific language impairment (SLI), affects 6%-7% of children with normal nonverbal intelligence and has evidence of a genetic basis in familial and twin studies. FOXP2 is located on chromosome 7q31, and studies of other disorders with speech and language impairment, including autism, have found linkage to this region. In the present study, samples from children with SLI and their family members were used to study linkage and association of SLI to markers within and around FOXP2, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of FOXP2. No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the CFTR gene and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2.     

A locus on chromosome 13 influences levels of TAFI antigen in healthy Mexican Americans

When activated, thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by modifying fibrin, depressing its plasminogen binding potential. Polymorphisms in the TAFI structural gene (CPB2) have been associated with variation in TAFI levels, but the potential occurrence of influential quantitative trait loci (QTLs) located elsewhere in the genome has been explored only in families ascertained in part through probands affected by thrombosis. We report the results of the first genome-wide linkage screen for QTLs that influence TAFI phenotypes. Data are from 635 subjects from 21 randomly ascertained Mexican American families participating in the San Antonio Family Heart Study. Potential QTLs were localized through a genome-wide multipoint linkage scan using 417 highly informative autosomal short tandem repeat markers spaced at approximately 10-cM intervals. We observed a maximum multipoint LOD score of 3.09 on chromosome 13q, the region of the TAFI structural gene. A suggestive linkage signal (LOD = 2.04) also was observed in this region, but may be an artifact. In addition, weak evidence for linkage occurred on chromosomes 17p and 9q. Our results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may contribute strongly to TAFI level variation in the general population, although several genes in other regions of the genome may also influence variation in this phenotype. Our findings support those of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, which identified a potential TAFI QTL on chromosome 13q in a genome-wide linkage scan in Spanish thrombophilia families.     

A genome‐wide sib‐pair scan for quantitative language traits reveals linkage to chromosomes 10 and 13

Although there is considerable evidence that individual differences in language development are highly heritable, there have been few genome‐wide scans to locate genes associated with the trait. Previous analyses of language impairment have yielded replicable evidence for linkage to regions on chromosomes 16q, 19q, 13q (within lab) and at 13q (between labs). Here we report the first linkage study to screen the continuum of language ability, from normal to disordered, as found in the general population. 383 children from 147 sib‐ships (214 sib‐pairs) were genotyped on the Illumina^® Linkage IVb Marker Panel using three composite language‐related phenotypes and a measure of phonological memory (PM). Two regions (10q23.33; 13q33.3) yielded genome‐wide significant peaks for linkage with PM. A peak suggestive of linkage was also found at 17q12 for the overall language composite. This study presents two novel genetic loci for the study of language development and disorders, but fails to replicate findings by previous groups. Possible reasons for this are discussed.     

Linkage of atopic dermatitis to chromosomes 4q22, 3p24 and 3q21

Atopic dermatitis (AD) is a common, itchy skin disease of complex inheritance characterized by dermal and epidermal inflammation. The heritability is considerable and well documented. To date, four genome scans have examined the AD phenotype, showing replicated linkage at 3p26-22, 3q13-21 and 18q11-21. Our previous AD scan showed evidence of linkage to loci at 3p and 18q, and furthermore at 4p15-14. In order to further investigate the genetic basis of AD, we collected and analysed a new Danish family sample consisting of 130 AD sib pair families (555 individuals including 295 children with AD). AD was diagnosed after clinical examination, AD severity was scored and specific IgE was determined. A linkage scan of chromosome 3, 4 and 18 was performed using 91 microsatellite markers. Linkage analyses were performed of dichotomous phenotypes and semi-quantitative traits including the AD severity score. We analysed the novel AD sample alone and together with the previously examined sample. AD severity showed a maximum Z-score of 3.7 at 4q22.1 suggesting the localization of a novel gene for AD severity. A maximum MOD score of 4.6 was obtained at 3p24 for the AD phenotype, providing the first significant linkage of AD at this locus. A maximum MLS score of 3.3 was obtained at 3q21 for IgE-associated AD, and evidence of linkage was also obtained at 3p22.2-21.31, 3q13, 4q35, and 18q12. The results presented should provide a firm basis for gene-targeting studies of AD and related disorders.     

Trait components provide tools to dissect the genetic susceptibility of migraine

The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.     

A Genomewide Scan Identifies Two Novel Loci Involved in Specific Language Impairment

Approximately 4% of English-speaking children are affected by specific language impairment (SLI), a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and concordance in monozygotic twins consistently exceeds that in dizygotic twins. However, like many behavioral traits, SLI is assumed to be genetically complex, with several loci contributing to the overall risk. We have compiled 98 families drawn from epidemiological and clinical populations, all with probands whose standard language scores fall 1.5 SD below the mean for their age. Systematic genomewide quantitative-trait–locus analysis of three language-related measures (i.e., the Clinical Evaluation of Language Fundamentals–Revised [CELF-R] receptive and expressive scales and the nonword repetition [NWR] test) yielded two regions, one on chromosome 16 and one on 19, that both had maximum LOD scores of 3.55. Simulations suggest that, of these two multipoint results, the NWR linkage to chromosome 16q is the most significant, with empirical P values reaching 10⁻⁵, under both Haseman-Elston (HE) analysis (LOD score 3.55; P=.00003) and variance-components (VC) analysis (LOD score 2.57; P=.00008). Single-point analyses provided further support for involvement of this locus, with three markers, under the peak of linkage, yielding LOD scores >1.9. The 19q locus was linked to the CELF-R expressive-language score and exceeds the threshold for suggestive linkage under all types of analysis performed—multipoint HE analysis (LOD score 3.55; empirical P=.00004) and VC (LOD score 2.84; empirical P=.00027) and single-point HE analysis (LOD score 2.49) and VC (LOD score 2.22). Furthermore, both the clinical and epidemiological samples showed independent evidence of linkage on both chromosome 16q and chromosome 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment.     

Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families

Childhood-onset asthma is frequently found in association with atopy. Although asthmatic children may develop IgE antibodies against variety of allergens, asthma is associated primarily with allergy to house-dust mites, molds, or other allergens. In this study, we conducted a genome-wide linkage search in 47 Japanese families (197 members) with more than two mite-sensitive atopic asthmatics (65 affected sib-pairs) using 398 markers. Multipoint linkage analysis was carried out for atopic asthma as a qualitative trait using the MAPMAKER/SIB program. We observed significant evidence for linkage with maximum lod scores (MLS) of 4.8 near the interleukin 12 B gene locus on chromosome 5q31-q33. In addition, suggestive evidence on 4q35 with MLS = 2.7 and on 13q11 with MLS = 2.4 was obtained. The other possible linkage regions included 6p22-p21.3 (MLS = 2.1), 12q21-q23 (MLS = 1.9), and 13q14.1-q14.3 (MLS = 2.0). Many of the linkage loci suggested in this study were at or close to those suggested by genome-wide studies for asthma in Caucasian populations. The present study suggests the contribution of the interleukin 12 B gene or nearby gene(s) to mite-sensitive atopic asthma and a considerable number of genetic variants common across Caucasians and Japanese populations contributing to asthma, although the relative importance of various variants may differ between the groups.     

Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait

Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.     

A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families

Generalized vitiligo is a common, autoimmune, familial-clustering depigmentary disorder of the skin and hair that results from selective destruction of melanocytes. Generalized vitiligo is likely a heterogeneous disease, with five susceptibility loci reported so far--on chromosomes 1p31, 6p21, 7q, 8p, and 17p13--in white populations. To investigate vitiligo susceptibility loci in the Chinese population, we performed a genomewide linkage analysis in 57 multiplex Chinese families, each with at least two affected siblings, and we identified interesting linkage evidence on 1p36, 4q13-q21, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12. Subsequently, to extract more linkage information, we investigated our initial genomewide linkage findings in a follow-up analysis of 49 new families and additional markers. Our initial genomewide linkage analysis and our subsequent follow-up analysis have identified a novel linkage to vitiligo on 4q13-q21, with highly significant linkage evidence (a nonparametic LOD score of 4.62 [P=.000003] and a heterogeneity LOD score of 4.01, under a recessive inheritance model), suggesting that 4q13-q21 likely harbors a major susceptibility locus for vitiligo in the Chinese population. We observed a minimal overlap between the linkage results of our current genomewide analysis in the Chinese population and the results of previous analyses in white populations, and we thus hypothesize that, as a polygenic disorder, vitiligo may be associated with great genetic heterogeneity and a substantial difference in its genetic basis between ethnic populations.     

A Novel Stratification Method in Linkage Studies to Address Inter- and Intra-Family Heterogeneity in Autism

Most genome linkage scans for autism spectrum disorders (ASDs) have failed to be replicated. Recently, a new ASD phenotypic sub-classification method was developed which employed cluster analyses of severity scores from the Autism Diagnostic Interview-Revised (ADI-R). Here, we performed linkage analysis for each of the four identified ADI-R stratified subgroups. Additional stratification was also applied to reduce intra-family heterogeneity and to investigate the impact of gender. For the purpose of replication, two independent sets of single nucleotide polymorphism markers for 392 families were used in our study. This deep subject stratification protocol resulted in 16 distinct group-specific datasets for linkage analysis. No locus reached significance for the combined non-stratified cohort. However, study-wide significant (P = 0.02) linkage scores were reached for chromosomes 22q11 (LOD = 4.43) and 13q21 (LOD = 4.37) for two subsets representing the most severely language impaired individuals with ASD. Notably, 13q21 has been previously linked to autism with language impairment, and 22q11 has been separately associated with either autism or language disorders. Linkage analysis on chromosome 5p15 for a combination of two stratified female-containing subgroups demonstrated suggestive linkage (LOD = 3.5), which replicates previous linkage result for female-containing pedigrees. A trend was also found for the association of previously reported 5p14-p15 SNPs in the same female-containing cohort. This study demonstrates a novel and effective method to address the heterogeneity in genetic studies of ASD. Moreover, the linkage results for the stratified subgroups provide evidence at the gene scan level for both inter- and intra-family heterogeneity as well as for gender-specific loci.     

Family history interview of a broad phenotype in specific language impairment and matched controls

The aim was to study a broader phenotype of language‐related diagnoses and problems in three generations of relatives of children with specific language impairment (SLI). Our study is based on a family history interview of the parents of 59 children with SLI and of 100 matched control children, exploring the prevalence of problems related to language, reading, attention, school achievement and social communication as well as diagnoses such as attention‐deficit hyperactivity disorder (ADHD), autism, Asperger syndrome, dyslexia, mental retardation, cleft palate and stuttering. The results show a spectrum of language‐related problems in families of SLI children. In all three generations of SLI relatives, we found significantly higher prevalence rates of language, literacy and social communication problems. The risk of one or both parents having language‐related diagnoses or problems was approximately six times higher for the children with SLI (85%) than for the control children (13%) (odds ratio = 37.2). We did not find a significantly higher prevalence of the diagnoses ADHD, autism or Asperger syndrome in the relatives of the children with SLI. However, significantly more parents of the children with SLI had problems with attention/hyperactivity when compared with the parents of controls. Our findings suggest common underlying mechanisms for problems with language, literacy and social communication, and possibly also for attention/hyperactivity symptoms.     

A posterior probability of linkage-based re-analysis of schizophrenia data yields evidence of linkage to chromosomes 1 and 17

OBJECTIVE: Linkage analysis using 22 Canadian pedigrees identified a promising schizophrenia candidate region on 1q23 with a maximum 2-point HLOD under a recessive model of 5.8 [Brzustowicz et al. 2000]. In the current study, we revisited this data set using a Bayesian linkage analysis technique, namely the posterior probability of linkage (PPL). METHODS: The PPL has been developed as an alternative to traditional linkage analysis. It differs from both LOD scores and 'non-parametric' methods in that it directly measures the probability of linkage given the data, and incorporates prior genomic information. RESULTS: As expected, PPL results for 1q23 supported the previously observed linkage, with an estimated multipoint PPL of 99.7%. However, the PPL supported two further results: a second peak on chromosome 1 at 1p13 with a multipoint with PPL of 70% and a chromosome 17 marker (D17S784 at 17q25) with a multipoint PPL of 44%. CONCLUSIONS: The PPL-based analysis presented has the advantage over other likelihood-based linkage methods in that it avoids maximization and produces a less complex view of the strength of evidence for linkage.