Dense linkage disequilibrium mapping in the 15q11-q13 maternal expression domain yields evidence for association in autism

Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5' introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11-q13.     

Evidence against linkage of schizophrenia to chromosome 5q11-q13 markers in systematically ascertained families.

Ten pedigrees systematically ascertained in Germany were tested for linkage to chromosome 5q11-q13. In order to replicate the previous report by Sherrington et al (1988), families with a bipolar family member were omitted from the lod score calculations, all diagnoses were based upon Research Diagnostic Criteria, and four different models of the affection status were calculated, including the model for which Sherrington et al calculated the highest lod scores. None of the families investigated showed a positive lod score. Using multipoint linkage analyses, we were able to exclude the region for which a positive linkage has been reported.     

Failure to replicate linkage between chromosome 5q11-q13 markers and schizophrenia in 28 families.

Sherrington et al. (1988) reported linkage between markers located on the 5q11-q13 region of chromosome 5 and schizophrenia in five Icelandic and two British families. To date, however, all attempts to replicate the initial finding have failed. Using three markers of chromosome 5, we have studied 28 additional French pedigrees. When our data were analyzed both with parametric (i.e., lod scores) and nonparametric methods, we found no evidence of linkage. Thus, we were unable to replicate the earlier report by Sherrington et al.     

Lack of linkage to chromosome 5q11-q13 markers in six schizophrenia pedigrees

We examined linkage between schizophrenia and five genetic markers on chromosome 5 in six pedigrees. Analyses were run considering the affected phenotype to be schizophrenia, schizophrenia plus a spectrum of related disorders, and these disorders plus any axis I diagnosis. None of the analyses were suggestive of linkage at any of the markers, either considering the pedigrees individually or in the aggregate. In our pedigrees, multipoint linkage analyses excluded much of the region that had supported linkage in an earlier study. These findings are consistent with other attempts to replicate the chromosome 5 linkage finding.     

The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13

A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.     

Albinism and developmental delay: the need to test for 15q11-q13 deletion

We report on a 17-month-old African girl with cutaneous and ophthalmologic features of oculocutaneous albinism type 2 as well as microcephaly, absent speech, and tremulous movements. Mutations of the P gene within the Angelman/Prader-Willi syndrome critical region at 15q11-q13 cause oculocutaneous albinism type 2. Comorbid oculocutaneous albinism and Angelman syndrome were suspected and confirmed by cytogenetics. Phenotypic features of Angelman syndrome or Prader-Willi syndrome in a patient with albinism should prompt further investigation.     

Pervasive developmental disorder and epilepsy due to maternally derived duplication of 15q11-q13.

Duplications of chromosome 15 have been reported in individuals with atypical autism, varying degrees of mental retardation, and epilepsy. The authors report the molecular analysis, neurophysiologic, and clinical evaluation of a 12-year-old boy with atypical autism and epilepsy due to a maternally derived 15q11-q13 duplication. Their findings suggest that this chromosomal region harbors genes for autism and possibly for partial epilepsy that may act in a dose-dependent manner.     

Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism

The purposes of this study were to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 (dup[15]) and autism and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p<0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% of idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p<0.04). The different spectrum and higher prevalence of developmental neuropathologic findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.     

Confirmation of linkage of oculopharyngel muscular dystrophy to chromosome 14q 11.2-q13

Oculopharyngeal muscular dystrophy is a late-onset, autosomally dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of oculopharyngeal muscular dystrophy to 14q11.2-q13 has been reported in a series of French Canadian families. Haplotype analysis in these data shows a single segregating disease chromosome, suggesting a founder effect in this population. We ascertained and sampled for linkage studies 5 multigenerational American families with oculopharyngeal muscular dystrophy. Four of the 5 families have known French Canadian ancestry while the fifth is of English/Scottish origin. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the families, confirming linkage to 14q11.2-q13. The English/Scottish family exhibited a different chromosomal haplotype for the oculopharyngeal muscular dystrophy alleles than did the families of French Canadian origin. These data suggest that this family may represent a second, possibly independent mutation in this disorder.     

Genetics of chromosome 15q13-q14 in schizophrenia.

Positive genetic linkage to the 15q13-q14 region has been found in 11 studies, and several association reports support this locus as a candidate region for schizophrenia. The locus is unusual in that it was first linked to an endophenotype found in schizophrenia, the P50 deficit, and subsequently to schizophrenia. There is also biological data showing that a candidate gene in the region, the alpha7 nicotinic receptor CHRNA7, plays a seminal role in the linked endophenotype, and is decreased in expression in the patient population. The 15q13-q14 region is complicated by a partial duplication of the CHRNA7 gene that includes exons 5-10 and considerable sequence downstream. Evidence from multiple studies supports a broad region of genetic linkage around the marker D15S1360.     

Tetrasomy 15q11-q13 identified by fluorescence in situ hybridization in a patient with autistic disorder

We report a female child with tetrasomy of the 15q11-q13 chromosomal region, and autistic disorder associated with mental retardation, developmental problems and behavioral disorders. Combining classical and molecular cytogenetic approaches by fluorescence in situ hybridization technique, the karyotype was demonstrated as 47,XX,+mar.ish der(15)(D15Z1++,D15S11++,GABRB3++,PML-). Duplication of the 15q proximal segment represents the most consistent chromosomal abnormality reported in association with autism. The contribution of the GABA receptor subunit genes, and other genes mapped to this region, to the clinical symptoms of the disease is discussed.     

Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13

CONTEXT: Traditionally, the search for genes involved in predisposition to major psychoses has proceeded with separate studies of schizophrenia and bipolar disorder. However, twin data suggest that, in addition to genes with specificity for these phenotypes, there exist genes that simultaneously influence susceptibility to schizophrenia, bipolar disorder, and schizoaffective disorder. OBJECTIVE: To undertake, to our knowledge, the first systematic search for such loci. DESIGN: Genomewide linkage scan. SETTING: Affected individuals were ascertained in the United Kingdom and Ireland from general psychiatric inpatient and outpatient services. PARTICIPANTS: The families were selected for linkage studies of either schizophrenia or bipolar disorder. Pedigrees were selected for the current analysis where there was at least 1 member with DSM-IV schizoaffective disorder, bipolar type. Within these pedigrees, individuals were coded as affected if they had been diagnosed with DSM-IV schizophrenia, schizoaffective disorder of bipolar type, or bipolar I disorder. A total of 24 pedigrees contributed 35 affected sibling pairs to the sample. METHOD: A 10-centimorgan genome scan using microsatellite markers was analyzed using MAPMAKER/SIBS software. RESULTS: A genomewide significant signal (LOD = 3.54) was observed at chromosome 1q42 (near D1S2800), and suggestive LOD scores were observed at chromosomes 22q11 (LOD = 1.96) and 19p13 (LOD = 1.85). No linkage was observed in these regions in our original schizophrenia or bipolar scans in individuals from the United Kingdom. CONCLUSIONS: Our linkage findings strongly support the existence of loci that influence susceptibility across the functional psychosis spectrum. The DISC1 gene lies within 2.5 megabases of our peak marker on chromosome 1q42 and has been previously implicated in schizophrenia, bipolar disorder, and, recently, schizoaffective disorder. Follow-up of this region should use samples enriched for cases of schizoaffective disorder. Our findings have similar implications for the search for genetic variation on chromosome 22q11 that influences susceptibility to psychosis.     

Mood-incongruent psychotic features in bipolar disorder: familial aggregation and suggestive linkage to 2p11-q14 and 13q21-33

OBJECTIVE: Mood-incongruent psychotic features in bipolar disorder may signify a more severe form of the illness and might represent phenotypic manifestations of susceptibility genes shared with schizophrenia. This study attempts to characterize clinical correlates, familial aggregation, and genetic linkage in subjects with these features. METHOD: Subjects were drawn from The National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative cohort, consisting of 708 families recruited at 10 academic medical centers. Subjects with mood-incongruent and mood-congruent psychotic features were compared on clinical variables. Familial aggregation was tested using a proband-predictive model and generalized estimating equations. A genome-wide linkage scan incorporating a mood-incongruence covariate was performed. RESULTS: Mood-incongruent psychotic features were associated with an increased rate of hospitalization and attempted suicide. A proband with mood-incongruence predicted mood-incongruence in relatives with bipolar I disorder when compared with all other subjects and when compared with subjects with mood-congruent psychosis. The presence of mood-incongruent psychotic features increased evidence for linkage on chromosomes 13q21-33 and 2p11-q14. These logarithm of the odds ratio (LOD) scores and their increase from baseline met empirical genome-wide suggestive criteria for significance. CONCLUSIONS: Mood-incongruent psychotic features showed evidence of a more severe course, familial aggregation, and suggestive linkage to two chromosomal regions previously implicated in major mental illness susceptibility. The 13q21-33 finding supports prior evidence of bipolar disorder/schizophrenia overlap in this region, while the 2p11-q14 finding is, to the authors' knowledge, the first to suggest that this schizophrenia linkage region might also harbor a bipolar disorder susceptibility gene.     

Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder

OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.