For the first time, researchers have observed how a variant of a single gene can lead to altered functional connections in the brain that may predispose an individual to cognitive dysfunction.
The gene, contactin-associated protein-like 2 (CNTNAP2), is expressed in the frontal and temporal lobes during development and is thought to assist in interactions important for cellular migration and the subsequent laminar organization of these areas. Some variants of the gene are associated with an increased risk of autism; specific language impairment; and other neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder, Tourette syndrome, and schizo-phrenia. These neuropsychiatric disorders all exhibit underlying abnormal frontal cortical circuitry connectivity.
Ashley A. Scott-Van Zeeland, Ph.D., and her colleagues at the University of California, Los Angeles, tied these lines of evidence together by conducting functional MRI scans of children with either a common or a less common, risk-conferring variant of the gene to determine how the gene contributes to brain development (Sci. Transl. Med. 2010 Nov. 3 [doi:10.1126/scitranslmed.3001344]). After performing this work as a graduate student at UCLA, Dr. Scott-Van Zeeland is now conducting her postdoctoral work at the Scripps Translational Science Institute, La Jolla, Calif.
In a discovery cohort of 16 typically developing children and 16 children with autism, carriers of a risk-conferring allele showed more neural activity in the medial prefrontal cortex during a learning task than did those with a nonrisk allele. The medial prefrontal cortex in nonrisk allele carriers was connected to more posterior cortical regions via a left-sided network (such as between the medial prefrontal cortex and the medial occipital and ventral temporal cortices), whereas in carriers of the risk allele there were stronger local connections to the right front cortex and there were widespread and bilateral connections to posterior regions.
The discrete left-sided frontotemporal network observed in nonrisk allele carriers overlapped with “regions known to be important in language processing, such as the IFG [inferior frontal gyrus] and superior temporal gyrus,” the investigators wrote.
They found similar results when they examined the effect of the allele in the children with and without autism, when they analyzed males only, and when they conducted the same scans during a different learning task in a replication cohort of 39 typically developing children.
The lack of an association between disease status and CNTNAP2 genotype “indicates that this variant mediates risk by modulating the continuum of normal brain function, as would be expected for intermediate phenotypes related to cognition or behavior,” the authors wrote.
They suggested that the approach of combining gene expression data with functional neuroimaging to understand the consequences of a known disease-associated gene on brain development “is likely to be of widespread utility in the elucidation of mechanism underlying disorders of human cognition.”
The study was supported in part by grants from the National Institutes of Health, the National Alliance for Autism Research, Autism Speaks, and the Whitehall Foundation. The researchers reported having no conflicts of interest.
Research report by Managing Editor, Jeff Evans
Functional connectivity maps in children with autism and in typically developing children showed that carriers of a CNTNAP2 “nonrisk” allele (top panel) had much greater connectivity within the frontal lobe than did carriers of a CNTNAP2 “risk” allele (bottom panel).
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