Nerve Cell Gene Linked to Autism
By Michael Smith, North American Correspondent, MedPage Today
Published: January 10, 2008
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

BALTIMORE, Jan. 10 — The risk for autism appears to increase in the presence of a common genetic variation on chromosome seven, especially when the condition is inherited from the mother, researchers here said.

The variant is a single nucleotide polymorphism (SNP) that’s found in 36% of the alleles of chromosome seven, according to Aravinda Chakravarti, Ph.D., of Johns Hopkins, and colleagues.

Dubbed rs7794745, the variant lies within a gene called contactin-associated protein-like 2 (CNTNAP2), Dr. Chakravarti and colleagues reported online in the American Journal of Human Genetics.

The gene, which encodes a protein involved in nervous system cellular interactions, had previously been associated with other neurological disorders, including cortical dysplasia-focal epilepsy and obsessive-compulsive disorder.

Also, two other papers in the journal reported links between autism and CNTNAP2. The reports come a day after researchers linked errors on chromosome 16 to the disorder. (See: Chromosome 16 Mutations Linked to Autism)

“CNTNAP2 is an excellent candidate gene for autism,” Dr. Chakravarti said.

“It encodes a protein that’s known to mediate interactions between brain cells and that appears to enable a crucial aspect of brain-cell development,” he added. “A gene variant that altered either of these activities could have significant impact.”

In a cohort of 72 families with multiple affected children — a total of 148 affected offspring and 292 other family members — the researchers performed a genome-wide scan for significant associations.

To reduce variation in the volunteers, the researchers required that the affected offspring meet a strict criterion of autism, rather than the broader “autism spectrum disorder.”

The gene scan found that a substitution of thymine for adenine at rs7794745 was significantly more common among those with autism (at P<2.14×10-5).

To confirm the finding, the researchers performed a separate genome-wide scan of 1,295 parent-child trios — this time with a broader definition of autism — and again found a significant over-transmission of the T allele (P<0.005) among the affected offspring.

Given the marked sex difference in autism — four times as many boys as girls are affected — the researchers also looked at which parent contributes the T allele to an autistic child.

The analysis found that the transmission frequency of the paternal T allele was 0.53 and the frequency of transmission of the maternal allele was 0.61, a difference that was significant at P<0.001, Dr. Chakravarti and colleagues said.

“This is a common variant,” Dr. Chakravarti said. “People inherit it all the time. Our finding that it’s associated with autism more often when it’s inherited from mothers is intriguing, but needs to be replicated.”

Meanwhile, using a language-based criterion — age at first word — another group of researchers found that a separate region of CNTNAP2 was associated with autism.

Daniel Geschwind, M.D., Ph.D., of the University of California at Los Angeles, and colleagues found that a SNP dubbed rs2710102 was significantly associated (P<0.028) with a delayed onset of speech.

In another study, researchers led by Matthew State, M.D., Ph.D., of Yale, found several rare variants in CNTNAP2 that appeared to be linked to autism.

Taken together, the three studies provide “unequivocal evidence” that disrupting CNTNAP2 leads to a subtype of autism spectrum disorder, said Dietrich Stephan, Ph.D., of the Translational Genomics Research Institute in Phoenix, in an accompanying commentary.

It’s now reasonable to say that people with autism combined with mutations in CNTNAP2 have “type 1 autism,” Dr. Stephan said.

The study was supported by the National Institute of Mental Health. Dr. Chakravarti did not report any potential conflicts.

Primary source: American Journal of Human Genetics
Source reference:
Arking DE, et al “A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism” Am J Hum Gen 2008; DOI: 10.1016/j.ajhg.2007.09.015.

Additional source: American Journal of Human Genetics
Source reference:
Stephan D, “Unraveling autism” Am J Hum Gen 2008; DOI: 10.1016/j.ajhg.2007.12.003.

Additional source: American Journal of Human Genetics
Source reference:
Alarcon M, et al “Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene” Am J Hum Gen 2008; DOI: 10.1016/j.ajhg.2007.09.005.

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MILTON, Ontario, Feb. 19 — Genes associated with an autism risk appear to be clustered in a region on chromosome 11, according to the largest study yet of families with a predisposition to the condition.
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In a study of more than 1,100 families, the Autism Genome Project Consortium, consisting of 137 investigators from 50 centers in 19 countries, has closed in on a stretch of the chromosome where genes involved with the neurotransmitter glutamate are known to lie, reported Peter Szatman, Ph.D., of McMaster University, Bernie Devlin, Ph.D., of the University of Pittsburgh, and colleagues, online in Nature Genetics.

“This study is by far the largest study ever conducted, in terms of both researchers and research subjects,” said Joachim Hallmayer, M.D., of Stanford, a co-author. The results point the way toward further studies, but are far from definitive, the authors acknowledged.

“While promising, these results need to be followed up with more refined genetic maps to home in on other specific candidate genes. We also need to look more closely at chromosomal anomalies in large samples of children with autism,” Dr. Hallmayer said.

The investigators conducted genetic analyses on 1,168 families in which two or more members had a diagnosis of autism, as defined by either the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule, or by clinical evaluation.

Genetic analysis of such a large sample may be particularly revealing the authors wrote, because autism has a strong genetic component. They pointed out that in twin studies, there is a concordance for autism of 60% to 92% among identical (monozygotic) twins, and up to 10% for dizygotic pairs.

“Although familial clustering in autism could reflect shared environmental factors, twin studies and the distribution of milder phenotypes in families favors a model involving multiple interacting loci,” the investigators wrote.

They hypothesized that autism is a joint or combined genetic affair in which various combinations of susceptibility alleles may play a role.

They used automated genotype analysis techniques to conduct genetic linkage analysis, which looked for specific genetic markers in the vicinity of a suspected autism susceptibility gene.

They also tracked chromosomal abnormalities among affected family members by looking at copy number variations, sub-microscopic genomic insertions, and deletions implicated in various disorders, including autism.

“Although we know autism is highly heritable, complex gene interactions and submicroscopic anomalies create a din of statistical noise that drowns out detection of signals from linked sites in the genome,” said Dr. Devlin. “To amplify these signals, we brought to bear gene chip technology with a huge sample, and also screened for these fine-level anomalies, factoring them into the analysis.”

There is also evidence that chromosomal abnormalities or genetic disorders such as fragile X syndrome or tuberous sclerosis syndrome, both of which involve aberrant glutamate signaling, may be involved in autism risk, they wrote.

Using the genetic linkage analysis, the authors found that the 11p12-p13 region of chromosome 11 was most closely linked to neuroligins, transmembrane proteins expressed on the postsynaptic cell that bind to presynaptic transmembrane proteins called β-neurexins.

The candidate genes are involved in the trans-synaptic transportation of glutamate, a major excitatory neurotransmitter.

“We also found a family with a deletion in a gene called neurexin 1 that appeared to correlate with a diagnosis of autism in this family,” Dr. Hallmayer said.

Two young girls in the family with the neurexin 1 deletion presented with typical autism, including characteristic developmental delays; one child appeared to be nonverbal, and that other had mild language regression.

Neurexin 1 encodes for a protein that facilitates interneuronal communication. Deficits or defects in glutamate function have been implicated previously in autism and other neurodevelopmental disorders.

“As for the chromosome 11 location, we think there is another susceptibility gene there and we are actively pursuing it,” said co-author Gerad Schellenberg, Ph.D., of the University of Washington in Seattle. “We are in the neighborhood and have a plan to find it.”

The study was funded by the non-profit organization Autism Speaks and by the National Institutes of Health. The authors disclosed no financial conflicts.

Primary source: Nature Genetics
Source reference: Szatmari P et al. “Mapping autism risk loci using genetic linkage and chromosomal rearrangements.” Nature Genetics doi:10.1038/ng1985

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