The Autism Genetic Resource Exchange: A Resource for the Study of Autism and Related Neuropsychiatric Conditions

The authors gratefully acknowledge the families and individuals who have contributed their biomaterials, time, and financial resources to AGRE, especially Marianne Toedtman, AGRE family recruiter; Ed Berry, phlebotomist; Andrew Smith, M.D., pediatric neurologist; and Nancy Jones,AGRE Web master.

Abstract

To the Editor: In this letter, we describe the Autism Genetic Resource Exchange (AGRE), a resource for the study of autism and pervasive developmental disorder (PDD). Autism presents within the first 3 years of life, is characterized by qualitative impairments in communication and social interaction—in the presence of restricted repetitive and stereotyped patterns of behavior, interests, and activities—and is part of a spectrum of disorders that includes Asperger syndrome and PDD (American Psychiatric Association American Psychiatric Association, 1994American Psychiatric Association Diagnostic and statistical manual of mental disorders. 4th ed-revised. American Psychiatric Association, Washington, DC1994Google Scholar). Estimates of the prevalence of autism in the general population ranges from 0.04% to >0.l% (Bryson et al. Bryson et al., 1988Bryson SE Clark BS Smith IM First report of a Canadian epidemiological study of autistic syndromes.J Child Psychol Psychiatry. 1988; 29: 433-445Crossref PubMed Scopus (228) Google Scholar; Gillberg et al. Gillberg et al., 1991Gillberg C Steffenburg S Schaumann H Is autism more common now than ten years ago?.Br J Psychiatry. 1991; 158: 403-409Crossref PubMed Scopus (204) Google Scholar). Twin and family studies have demonstrated that the genetic contribution to autism and PDD is significant, with an MZ-twin concordance of 60%–90% and a 45- to 150-fold increase in risk to siblings (Ritvo et al. Ritvo et al., 1989Ritvo ER Mason-Brothers A Freeman BJ Pingree C Jenson WR McMahon WM Petersen PB Jorde LB Mo A Ritvo A The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling.Am J Psychiatry. 1989; 146: 1032-1036PubMed Google Scholar; Jorde et al. Jorde et al., 1990Jorde LB Mason-Brothers A Waldmann R Ritvo ER Freeman BJ Pingree C McMahon WM Petersen B Jenson WR Mo A The UCLA-University of Utah epidemiologic survey of autism: genealogical analysis of familial aggregation.Am J Med Genet. 1990; 36: 85-88Crossref PubMed Scopus (44) Google Scholar; Bailey et al. Bailey et al., 1995Bailey A Le Couteur A Gottesman I Bolton P Simonoff E Yuzda E Rutter M Autism as a strongly genetic disorder: evidence from a British twin study.Psychol Med. 1995; 25: 63-77Crossref PubMed Scopus (1780) Google Scholar). Thus, molecular genetic studies of autism-spectrum disorders are likely to contribute significantly to our understanding of this condition, as the recent results of several independent genome scans suggest (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 (476) Google Scholar; Barrett et al. Barrett et al., 1999Barrett S Beck JC Bernier R Bisson E Braun TA Casavant TL Childress D et al.An autosomal genomic screen for autism: collaborative linkage study of autism.Am J Med Genet. 1999; 88: 609-615Crossref PubMed Scopus (307) Google Scholar; Philippe et al. Philippe et al., 1999Philippe A Martinez M Guilloud-Bataille M Gillberg C Rastam M Sponheim E Coleman M Zappella M Aschauer H van Malldergerme L Penet C Feingold J Brice A Leboyer M Genome-wide scan for autism susceptibility genes: Paris Autism Research International Sibpair Study.Hum Mol Genet. 1999; 8: 805-812Crossref PubMed Scopus (418) Google Scholar; Risch et al. Risch et al., 1999Risch N Spiker D Lotspeich L Nouri N Hinds D Hallmayer J Kalaydjieva L et al.A genomic screen of autism: evidence for a multilocus etiology.Am J Hum Genet. 1999; 65: 493-507Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar). AGRE has been developed as a joint effort of the Cure Autism Now (CAN) Foundation and the Human Biological Data Interchange (HBDI), to facilitate collaborative genetic research into the etiology of autism and PDD and to make biomaterials from well-characterized families with autism widely available to the scientific community, so as to accelerate research. Since genetic studies of complex neuropsychiatric conditions are limited by the large sample sizes needed to attain adequate power (Lander and Kruglyak Lander and Kruglyak, 1995Lander E Kruglyak L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar; Risch and Merikangas Risch and Merikangas, 1996Risch N Merikangas K The future of genetic studies of complex human diseases.Science. 1996; 273: 1516-1517Crossref PubMed Scopus (4160) Google Scholar), the consolidation of large numbers of families into one collection that is made available to researchers at a fraction of the cost originally incurred in their ascertainment and collection is of great value to the community. One unique feature of AGRE, which has enabled the rapid ascertainment of large numbers of families, has been the development of a protocol and the infrastructure to conduct the majority of the evaluations and blood draws in the families' homes. This process may prove useful for more-rapid family ascertainment in studies of other neuropsychiatric conditions (AGRE Web site). To date, ∼400 multiplex families with autism and PDD are in various stages of clinical evaluation, with DNA collection completed (table 1). Both an online and a hard-copy catalogue are available, containing the pedigrees in the collection, with notations of affectation status and basic phenotypic features, such as language delay. A sample pedigree is depicted in figure 1. Biomaterials from 343 of these completed families are currently available to the scientific research community, and this resource continues to expand, with the goal of 500 families by the end of the year 2001. Family biomaterials for the AGRE program are housed at the HBDI Repository at Rutgers University, under the direction of Jay Tischfield. Quality-controlled samples, including immortalized cell lines (1 × 106 cells/ampoule), 20-μg aliquots of DNA, and 50-μl aliquots of sera, are available to the research community by simple application, which requires proof of institutional review board (IRB) approval. Samples are available to academia and industry, and significant discounts, as well as limited grants to support academic use of the resource, are available to academic researchers through the CAN Foundation. To facilitate collaboration, free samples are available to researchers who deposit their collections in AGRE through the Sharing Researcher Program.Table 1Patient Recruitment and AvailabilityStatusCurrentProjected 2001Recruited:aConsented and scheduled for ADI and blood draw. Families428500 Individuals1,9782,250Completed:bADI complete, biomaterials complete, quality controlled and available for distribution. Families343420 Individuals1,5951,890In process:cIncomplete biomaterials or ADI. Families8580 Individuals496360a Consented and scheduled for ADI and blood draw.b ADI complete, biomaterials complete, quality controlled and available for distribution.c Incomplete biomaterials or ADI. Open table in a new tab Scientific oversight for the program is provided by a Steering Committee, which includes researchers from the fields of genetics and autism. Human subjects protection oversight is provided by the IRB at the University of Pennsylvania School of Medicine. In addition to providing researchers with biomaterials, a major effort has been undertaken to develop a state-of-the-art, Internet-accessible database of detailed clinical information. Phenotypic assessment is ongoing and includes the two examinations that are completed by all of the NIH autism collaborative groups: 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 (6298) Google Scholar) and the Autism Diagnostic Observational Schedule (ADOS) (Lord et al. Lord et al., 2000Lord C Risi S Lambrecht L Cook Jr, EH Leventhal BL DiLavore PC Pickles A Rutter M The autism diagnostic observation schedule-generic: a standardized observation of communicative and social behavior associated with the spectrum of autism.J Autism Dev Disord. 2000; 30: 205-223Crossref PubMed Scopus (5120) Google Scholar). All ADI and ADOS raters undergo ongoing reliability checks to prevent any drift in diagnosis (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 (6298) Google Scholar, Lord et al., 2000Lord C Risi S Lambrecht L Cook Jr, EH Leventhal BL DiLavore PC Pickles A Rutter M The autism diagnostic observation schedule-generic: a standardized observation of communicative and social behavior associated with the spectrum of autism.J Autism Dev Disord. 2000; 30: 205-223Crossref PubMed Scopus (5120) Google Scholar). In addition, photographic dysmorphology, physical and neurological examination, and medical and family history are being collected by pediatric neurologists. Probands with possible secondary autism resulting from perinatal trauma, from an identified genetic syndrome, or from other medical causes are noted, although this is only a small percentage of cases. Currently, the ADI data and a subset of the ADOS data, both coded for confidentiality, are available online for researcher access through the AGRE Web site. Online phenotypic databases for the remainder of the data collected are being developed and will be available in ≤6 mo. More information on the timeline of data and material collection is available at the Web site. We are striving to improve the utility of AGRE, and user feedback is an important element in this process. Fragile-X testing is conducted in all families (Brown et al. Brown et al., 1986Brown WT Jenkins EC Cohen IL Fisch GS Wolf-Schein EG Gross A Waterhouse L Fragile X and autism: a multicenter survey.Am J Med Genet. 1986; 23: 341-352Crossref PubMed Scopus (131) Google Scholar), and cytogenetic analysis—including FISH for 15q and telomere screening—is commencing. Of 220 families tested, 3 have subjects that carry a fragile-X expansion (1.3%; W. T. Brown, unpublished data). A genome scan at an average 10-cM resolution has been completed on the first 132 families in the collection (T. C. Gilliam, personal communication), and genotype data from 188 families are available online at the AGRE Web site. As genome scans on additional families are completed, these data will be updated regularly, and investigators accessing these data will be notified of the updates automatically. More information regarding this resource, including pricing of samples and access to the resource, can be obtained from the CAN Foundation and AGRE Web sites, or by contacting the authors. We gratefully acknowledge the families and individuals who have contributed their biomaterials, time, and financial resources to AGRE, especially Marianne Toedtman, AGRE family recruiter; Ed Berry, phlebotomist; Andrew Smith, M.D., pediatric neurologist; Paul Law, M.D., M.P.H., for database development; and Nancy Jones, AGRE Web master. We specifically thank Sallie and Tom Bernard, for their generous financial support of AGRE, and the Schering-Plough Research Institute and Pfizer Inc., for their contributions to AGRE. We also thank Maricela Alarcon, Ph.D., for her error checking and advice; Jianjun Liu, Ph.D., for updating of the genotyping data; and scientists who have started to utilize AGRE, for their helpful comments and criticism. The members of the AGRE Steering Committee are: W. Ted Brown, New York State Institute for Basic Research in Developmental Disabilities, Staten Island; Maya Bucan, University of Pennsylvania, Philadelphia; Joseph Buxbaum, Mt. Sinai School of Medicine, New York; T. Conrad Gilliam, Columbia University Genome Center, New York; David A. Greenberg, Mt. Sinai School of Medicine, New York; David H. Ledbetter, University of Chicago, Chicago; Bruce L. Miller, University of California, San Francisco; Stanley F. Nelson, UCLA School of Medicine, Los Angeles; Jonathan Pevsner, Kennedy Krieger Institute, Baltimore; Jerome I. Rotter, Cedars-Sinai Medical Center, Los Angeles; Carol Samango-Sprouse, Children's National Medical Center, Baltimore; Gerard D. Schellenberg, University of Washington and Veterans Affairs Medical Center, Seattle; Rudolph E. Tanzi, Massachusetts General Hospital, Boston; and Kirk C. Wilhelmsen, University of California, San Francisco.