James S. Sutcliffe - US grants

Autism is a severe neurodevelopmental disorder characterized by social interaction and language deficits, and behavior abnormalities, including repetitive or stereotyped actions. Autism is common, affects approximately 2-5/10000 children, and is often seen with accompanying neurological features such as mental retardation and seizures. Autism has a complex etiology, with evidence from pedigree, twin and sibling studies indicating a strong genetic component. Two categories of investigation point to the chromosome 15q11-q13 region deleted in Prader-Willi syndrome and Angelman syndrome (AS) as harboring a locus or loci for autism. Large duplications, affecting maternally-derived chromosomes and resulting in three or four copies of 15q11-q13, are consistently detected in the autistic population; this implies a potential role of genomic imprinting and may indicate that disruption of normal, possibly imprinted , gene dosage of this region can confer susceptibility to autism. Independent studies support linkage of autism in multiplex families to 15q11- q13 and elevated recombination in a 15q11-q13 maternal recombination hotspot, in autism families. DNA marker genotyping for linkage studies reveals null and three allele genotypes at several markers within 15q11-q13, in autism families, suggesting smaller genomic rearrangements. We characterize a 5-kb genomic deletion encompassing one marker as a cause for these results, and this deletion is present at a significantly higher frequency in autism families compared to controls, suggesting an association. This potential susceptibility marker will be explored further for relevance to autism. Maternal-specificity of large duplications may point directly to imprinted, maternally-expressed genes, of which the AS gene termed UBE3A, is an example. The linkage and related data, however, appear to indicate a slightly more telomeric location for an autism locus, within a region containing multiple neurological and positional candidates and unresolved imprinting status. Uniting the duplication and linkage data could involve a possible hypermorphic susceptibility allele. The project will correlate genomic sequence and contigs for the key region, with large duplications and smaller defects, genes, simple-sequence repeat markers, and developing polymorphisms. Genes in the autism candidate region will be analyzed for expression and imprinting in the brain, screened for functional sequence variation, and variants analyzed in simplex and multiplex families to test for involvement in autism.

[unreadable] DESCRIPTION (provided by applicant): Autism is a neuropsychiatric disorder exhibiting a complex genetic etiology with significant clinical and locus heterogeneity. Duplications affecting chromosome 15q11-q13 are the most common cytogenetic abnormality in autism, and linkage and association studies indicate that this region is involved in inherited susceptibility for autism in chromosomally normal families. We propose dissecting the genetic basis for inherited risk associated with 15q11-q13 in autism by (1) employing a thoroughly phenotyped dataset of 365 parent-child trios and 330 multiplex families; (2) characterization of duplicon-mediated rearrangements and potential epigenetic effects; (3) identifying genetically more homogeneous subgroups with which to detect and characterize genetic effects; and (4) performing high-resolution linkage disequilibrium mapping using single nucleotide polymorphisms (SNPs) to define haplotypes for use in analysis of allelic effects in these families. Our goal will be accomplished through five specific aims. (1) Recruitment and detailed clinical assessment of singleton families using a standardized panel of diagnostic instruments and algorithms. (2) Characterization of chromosomal rearrangements involving 15q and examination of potential epigenetic dysregulation of imprinted expression. (3) Construction of a complete haplotype map for the 15q11-q13 candidate region and identification of a reduced set of SNPs for discrimination of all common (>5%) haplotypes. (4) Application of individual markers and multi-marker haplotypes to characterize allelic and epistatic effects in these autism families. (5) Identification of 15q11-q13 allelic variants in autism and preliminary characterization of the functional effect of those variations. Associated haplotype blocks and/or functionally-significant regions within candidate genes will be screened to identify likely functional variants. We will evaluate the significance of any genetic findings by examination of independent datasets through collaboration with other groups. The result of these efforts will be an understanding of how 15q11-q13 contributes to inherited susceptibility in autism and the broader autism spectrum. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Autism is a neuropsychiatric disorder exhibiting a complex genetic etiology with significant clinical and locus heterogeneity. Autism predominantly affects males compared to females, leading to significant interest into the etiology of sex bias in disease risk or expression. We propose to pursue promising initial studies implicating a network of loci critical for the development and regulation of central serotonergic function. We will determine the nature and extent of susceptibility associated with the serotonin (5-HT) transporter (SLC6A4) and integrin beta3 (ITGB3) loci, which lie within a chromosome 17q11-21 region conferring significant male-biased genetic risk in autism. Similarly, the 5-HT-1A receptor gene (HTR1A) shows allelic association that is more pronounced in male probands. The 5-HT transporter (SERT) and 5-HT1A receptor are lynchpins in the control of serotonin concentration and function in the CNS, and emerging data reveals the synergistic actions of SERT and ITGB3 in mediating elevated 5-HT levels in the circulation, a hallmark of many patients with autism. We propose to (1) fully elaborate an allelic heterogeneity framework for disease risk at SLC6A4, (2) the functional nature of putative SLC6A4 risk alleles, (3) characterize genetic risk indexed by significant association with functional alleles at ITGB3 and HTR1A, (4) determine the degree to which allelic interaction or epistasis involving this network may contribute to disease risk and abnormal function, (5) develop a rich phenotypic dataset on additional autism families to more fully understand the genotype-phenotype correlations attributable to susceptibility alleles identified in this project, (6) explore the extent of disease risk in relation to other key molecules in this network by testing the hypothesis that risk alleles also exist at loci encoding these proteins. Through this project, we will substantially advance our understanding of how genetic variation affects expression and function of proteins controlling development and interconnection of a vital neurotransmitter system that is implicated in the etiologies of autism and many other disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This collaborative application is submitted in response to RFA MH-09-171. The root causes of autism remain unknown, limiting efforts to understand disease heterogeneity, diagnose cases, and prevent and treat disease. Epidemiological findings have repeatedly and unequivocally determined that heritable variation in DNA plays a substantial role in the etiology of autism and autism spectrum disorders, yet traditional efforts to identify the genetic basis of this striking heritability have met with very limited success to date and have therefore provided limited insight into disease biology. We propose here an unprecedented partnership between expert large- scale sequencing centers (at the Baylor College of Medicine and the Broad Institute of MIT and Harvard) and a collaborative network of research labs focused on the genetics of autism (brought together by the Autism Genome Project and the Autism Consortium). These groups will work together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism, first through a detailed examination of 1000 genes implicated by previous genetic studies or postulated to be functionally relevant, and later, as the technology continues to advance, through unbiased whole-genome sequencing. The goal is to conclusively identify which genes harbor individual or collections of rare DNA variants that predispose to autism, and thus translate the abstract heritability into solid biological clues to disease pathogenesis that can be studied molecularly and approached therapeutically. These efforts and their follow-up, which will be performed on thousands of autism families collected by the autism research groups and being provided with phenotype data to NIMH repositories, will form the cornerstone of autism genetic research going forward.

Abstract: We propose in this application to use truly unique resources available to the Vanderbilt University research community to identify and characterize genetic risk factors for neuropsychiatric disorders. Our overarching hypothesis is that co-morbid phenotypes that cut across neuropsychiatric disorders can be used to identify more homogeneous genetic risk factors that will also be cross-cutting for neuropsychiatric diseases. To address this hypothesis, we will harness the long-standing strengths in neuroscience at Vanderbilt including extensive expertise in conducting in vivo and in vitro experimental validation studies, the strong team of investigators with long-standing research programs in key co-morbid phenotypes and neuropsychiatric disease, and our track record in developing and applying novel integrative approaches for genome investigation. The clinical data warehouse at Vanderbilt is called the Synthetic Derivative (SD), and contains continuously updated electronic health records (EHR) on more than 2,500,000 individuals. DNA samples are available on more than 217,000 of the individuals in the SD through BioVU, the biobank at Vanderbilt University. Individuals with more longitudinal data some going back as long as 20-30 years have been prioritized for genome investigation, and genome interrogation (GWAS or whole genome sequencing) will be available on > 120,000 of these subjects in 2018. The SD provides unprecedented power for characterizing cross-cutting comorbidities for neuropsychiatric disorders, and the large number of BioVU samples with genome interrogation coupled with the novel analytic approaches we have devised to optimize genome investigations in BioVU create a dynamic engine for discovery research. Our specific aims are to: 1) Use EHR data on more than 2,500,000 individuals to investigate the relationship between neuropsychiatric disorders and comorbid phenotypes shared among multiple of these disorders; 2) Use the novel PrediXcan approach to identify genes for which genetically predicted expression is significantly associated with neuropsychiatric disease, neuropsychiatric disease plus comorbidity, or comorbidity for more than 120,000 samples in BioVU; and 3) Prioritize genes for validation using improved network and pathway analyses, and then experimentally validate genes implicated in neuropsychiatric and comorbid phenotypes.