Multi-Center Research Team Discovers Genetic Link to Autism
In a multi-center study of 222 families in the United States, scientists have found a strong genetic link to autism on chromosome 7. The study, in which five large universities participated, was part of the National Institutes of Health Collaborative Programs of Excellence in Autism, or CPEA. The results were published in the August, 2006 issue of Molecular Psychiatry.
Autism, a neurodevelopmental disorder in which a child exhibits impaired development in social interaction and language, and repetitive, or a restricted range of, activities, affects up to l.5 million Americans, and is the nation’s fastest growing development disability.
Statistics show that most children develop symptoms of autism in their first year, but about 25 percent seem to develop normally, then show regression in the second and third years of life. Previous studies indicate that there is a genetic role in autism: if one identical twin has autism, the other is 69 percent -95 percent more likely to have the disorder also. Fraternal twins are only 0 percent -24 percent more likely to share the disorder, similar to non-twin siblings at 2.8 percent-7 percent more likely .
Specific Genetic Link to Autism Is Sought
The search for a genetic link to autism has been elusive. According to the researchers of the current study, the extent of genetic variation in autism is unknown, and if extensive, could make it very difficult to detect specific locations in the genome. But they suggest that the differences in results across previous linkage studies may also reflect the wide variety of study designs and the inconsistency of diagnostic criteria used.
In this study, the researchers used the strictest diagnosis of autism in affected individuals. In previous linkage studies, autism has been associated with various regions of chromosomes and, more recently, with relatively rare single gene disorders, such as fragile X syndrome, the most commonly inherited form of mental impairment according to the Fragile X Research Foundation.
Among the regions that have been identified in various studies are 1p (“p” signifying the long arm of the chromosome), 2 q (the “q” signifying the short arm of the chromosome), 7q, 17q, and 19q, with the 2q, 7q and 17q regions giving the strongest signals.
How the Study Population Was Selected
Recruitment of the 222 families was conducted by five participating research institutions, including the University of Washington Autism Center, the University of California at Irvine, the University of Utah, the University of Rochester and the University of Pittsburgh.
All affected individuals were assessed using the ADI-R (Autism Diagnostic Interview-Revised) and ADOS-G [Autism Diagnostic Observation Schdule – Generic] , combined with a clinical diagnosis based on DSM-IV criteria . Children were given an age-appropriate standardized intellectual evaluation. The final diagnosis was based on the National Institute of Child Health and Development (NICHD) CPEA diagnostic criteria.
Of the total study participants, 169 families had two or more siblings identified by the strictest diagnosis of autism. In the other 53 families, two or more siblings met the broader criteria for autism, pervasive developmental disorder and/or autism spectrum disorder. Some families included additional children with so-called broader autism phenotype, who were not included in the affected sib-pair linkage analyses, but were included in quantitative trait analyses of language development in the children , such as age of first word and age of first phrase.
The presence of regression, defined as the appearance of autism in the second or third year, was also determined. In addition, the researchers conducted analyses based on families with only male affected children versus families where there was at least one affected female.
A Strong Link to Chromosome 7q Conforms to Previous Studies
To identify regions of the genome containing autism genes, the researchers performed a genome-wide linkage scan using the genotypes (the genetic make-ups) of the individuals in the participating 222 families. The strongest link to autism was observed on chromosome 7q, overlapping positive results of analyses from the International Molecular Genetic Study of Autism Consortium, and other previous studies.
The research team attempted to duplicate gender-related links found on chromosomes 4, 7 and 17 in previous studies. They found the strongest signal from the primary genome scan of both male and female families was seen at a localized point on chromosome 7, with a stronger result from the male only families compared to female only families. The strongest male only signal was on chromosome 11 and for the female only group on chromosome 4, the latter comparable to findings from the Autism Genetic Resource Exchange consortium. The team observed no signal for either sex on chromosome 17.
The researchers also sought to replicate previous studies related to regression, where linkage signals had been observed on chromosomes 7 and 21. The families were analyzed in two groups, those with at least one affected individual with regression versus families with no cases of regression. The researchers observed modest linkage signals for the regression-positive group on chromosomes 10 and 14, and more significant peaks in the regression-negative group on chromosomes 3 and 4. Using language acquisition data as a quantitative trait in their linkage analysis, the researchers observed a chromosome 9 signal among the regression-positive group.
Discussion and Caveats
Because of the high male -to- female ratio of autism ( three-to-four males to every female with the disorder), the researchers suggest that the observed differences in gender linkages present the possibility that there may be male- and female-specific genes, or more likely, that the ability of some susceptibility genes to effect male versus female subjects is significantly different.
When only regression-negative families were considered, evidence for genetic linkage on both chromosomes 4 and 3 increased markedly, suggesting differences in the genetics underlying regression versus the genetics of early developing autism in non-regression subjects.
In comparing their study results to other studies, the researchers believe they “provided strong support for a chromosome 7 autism locus and lesser but still compelling support for loci on chromosomes 3,4 and 11.” They were unable, however, to reproduce significant signals reported by others previously. They believe this may be explained by the fact that not all studies have the large sample sizes needed and the possibility that some of the smaller signals, including those reported in the current study, may have been false-positive results.
The variation in findings may be due to differences across studies in the definition of traits and in the gathering of family history. The research team tried to minimize the variations by using a rigorous diagnostic protocol and the strictest criteria for autism. But some signals were more significant for the broad diagnosis than for the strict diagnosis of autism. Thus, the researchers believe that the strict criteria used may actually have reduced the evidence in favor of genetic linkage by eliminating some families or individuals that would have added to the evidence for linkage.
The researchers call ed for larger sample sizes for linkage identification and replication to establish their significance in the field, but not at the expense of increasing the heterogeneity, or variation of characteristics, among the study groups. They believe it may be useful to identify subgroups of phenotypes, the observable sets of traits or characteristics of people as determined by genes and the environments in which they developed.
Analysis of autism endophenotypes, which are characteristics unseen by the unaided eye that are normally associated with a condition but are not direct symptoms of the disorder, may permit mapping of genetic locations that contribute to the specific domains of autism (social interaction, language, restricted range of activities) that would be difficult to genetically map using only diagnosis as the trait.
Finally, additional tools may be needed and designed specifically for quantitative traits related to autism in both affected and normal individuals so that phenotypic information from all family members can be used to increase the power to detect linkage.
Authors: Schellenberg GD1,2,3,4, Dawson G5,6, Sung YJ7, Estes A6, Munson J5, Rosenthal E8, Rothstein J8, Flodman P9, Smith M10, Coon H10, Leong L1,2, Yu C-E1,2, Stodgell C11, Rodier PM11, Spence MA9, Minshew N12, McMahon WM10, Wijsman EM7,8
1Geriatrics Research Education and Clinical Center, Puget Sound Veterans Affairs Medical Center, Seattle, WA; 2Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA; 3Department of Neurology, University of Washington, Seattle, WA; 4Department of Pharmacology, University of Washington, Seattle, WA; 5Department of Psychology and the Center on Human Development and Disability, University of Washington, WA; 6Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA: 7Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA; 8Department of Biostatistics, University of Washington, Seattle, WA; 9Department of Pediatrics, University of California, Irvine, CA; 10Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of Utah, Salt Lake City, UT; 11Department of OB/GYN, University of Rochester Medical Center, Rochester, NY; 12Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
For further reading:
1. International Molecular Genetic Study of Autism Consortium. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570-581.
2. Lamb JA, Barnby G, Bonora E, Sykes N, Bacchelli E, Blasi F et al. Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J Med Genet 2005; 42: 132-137.
3. Stone JL, Merriman B, Cantor RM, Yonan AL, Gilliam TC, Geschwind DH et al. Evidence for sex-specific, risk alleles in autism spectrum disorder. Am J Hum Genet 2004; 75: 1117-1123.
4. Shao YJ, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA et al. Genomic Screen and follow-up analysis for autistic disorder. Am J Med Genet 2002; 114: 99-105.
5. Yonan AL, Alarcon M, Chang R, Magnusson PKE, Spence SJ, Palmer AA et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 2003; 73: 886-897.
6. IMGSAC. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum MolGenet 1998; 7:571-578.
7. Molloy CA, Keddache M, Martin LJ. Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry 2005; 10: 741-746.
8. Sung YJ, Dawson G, Munson J, Estes A, Schellenberg GD, Wijsman EM. Genetic investigation of quantitative traits related to autism: use of multivariate polygenic models
with ascertainment adjustment. Am J Hum Genet 2005; 76: 68-81.
9. Dawson G, Estes A, Munson J, Schellenberg GD, Bernier R, Abbott R et al. Quantitative assessment of autism symptoms in autism probands and parents: Broader Phenotype Autism Symptom Scale. J Autism Dev Disord 2006 (in press).
Autistic people have fought the inclusion of ABA in therapy for us since before Autism Speaks, and other non-Autistic-led autism organizations, started lobbying legislation to get it covered by insurances and Medicaid.
ABA is a myth originally sold to parents that it would keep their Autistic child out of an institution. Today, parents are told that with early intervention therapy their child will either be less Autistic or no longer Autistic by elementary school, and can be mainstreamed in typical education classes. ABA is very expensive to pay out of pocket. Essentially, Autism Speaks has justified the big price tag up front will offset the overall burden on resources for an Autistic’s lifetime. The recommendation for this therapy is 40 hours a week for children and toddlers.
The original study that showed the success rate of ABA to be at 50% has never been replicated. In fact, the study of ABA by United States Department of Defense was denounced as a failure. Not just once, but multiple times. Simply stated: ABA doesn’t work. In study after repeated study: ABA (conversion therapy) doesn’t work.
What more recent studies do show: Autistics who experienced ABA therapy are at high risk to develop PTSD and other lifelong trauma-related conditions. Historically, the autism organizations promoting ABA as a cure or solution have silenced Autistic advocates’ opposition. ABA is also known as gay conversion therapy.
The ‘cure’ for Autistics not born yet is the prevention of birth.
The ‘cure’ is a choice to terminate a pregnancy based on ‘autism risk.’ The cure is abortion. This is the same ‘cure’ society has for Down Syndrome.
This is eugenics 2021. Instead of killing Autistics and disabled children in gas chambers or ‘mercy killings’ like in Aktion T4, it’ll happen at the doctor’s office, quietly, one Autistic baby at a time. Different approaches yes, but still eugenics and the extinction of an entire minority group of people.
Fact: You can’t cure Autistics from being Autistic.
Fact: You can’t recover an Autistic from being Autistic.
Fact: You can groom an Autistic to mask and hide their traits. Somewhat. … however, this comes at the expense of the Autistic child, promotes Autistic Burnout (this should not be confused with typical burnout, Autistic Burnout can kill Autistics), and places the Autistic child at high risk for PTSD and other lifelong trauma-related conditions.
[Note: Autism is NOT a disease, but a neurodevelopmental difference and disability.]
Fact: Vaccines Do Not Cause Autism.