About 90 percent of autism spectrum disorders have suspected genetic causes but few genes have been identified so far. Now, leading an international team, Johns Hopkins researchers have identified several genetic links to autism, chief among them a variant of semaphorin 5A, whose protein product controls nerve connections in the brain.
Semaphorin 5A had already been known to help guide growing neurons to the right connecting points in the brain during fetal development. To verify that semaphorin 5A plays a role in autism, the researchers looked at brain tissue samples from the Autism Tissue Program and the Harvard Brain Bank, and found the amount of the semaphorin 5A protein to be significantly reduced in autism brains compared to non-autism brains. The finding suggests that autism could result from differences in how nervous system connections are made in the brain.
Publishing this week in Nature, the team also reports additional evidence that many rare and common genetic variants contribute to autism.
"The biggest challenge to finding the genes that contribute to autism is having a large and well-studied group of patients and their family members both for primary discovery of genes and to test and verify the discovery candidates," says Aravinda Chakravarti, Ph.D., professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "This latest finding would not have been possible without these many research groups and consortia pooling together their patient resources. Of course, they would not have been possible without the genomic scanning technologies either."
Using genome-wide scanning technologies, the team "read" the genomes of family members, among whom more than one individual was diagnosed with an autism spectrum disorder. In all, they studied 1,031 nuclear families and 1,553 affected children, looking at 500,000 spots in the genome — so-called single nucleotide polymorphisms or SNPs — for differences that stood out in the DNA. The information was collected from two sources: the Autism Genetic Resource Exchange (AGRE) and the US National Institute of Mental Health.
Specifically, they performed two types of genetic analysis to identify genes with both rare and common genetic variations that might contribute to autism. By studying siblings with autism, the authors teased out four regions of the human genome — on chromosomes 6, 15, 17 and 20 — where rare variants in yet unidentified genes appear to contribute to autism susceptibility. Additionally, after examining the patterns of genetic similarities and differences in unrelated people with autism, the researchers discovered a common variation near only one gene, semaphorin 5A.