Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2

Abstract

Genetic studies are rapidly identifying variants that shape risk for disorders of human cognition, but the question of how such variants predispose to neuropsychiatric disease remains. Noninvasive human brain imaging allows assessment of the brain in vivo, and the combination of genetics and imaging phenotypes remains one of the only ways to explore functional genotype-phenotype associations in human brain. Common variants in contactin-associated protein-like 2 (CNTNAP2), a neurexin superfamily member, have been associated with several allied neurodevelopmental disorders, including autism and specific language impairment, and CNTNAP2 is highly expressed in frontal lobe circuits in the developing human brain. Using functional neuroimaging, we have demonstrated a relationship between frontal lobar connectivity and common genetic variants in CNTNAP2. These data provide a mechanistic link between specific genetic risk for neurodevelopmental disorders and empirical data implicating dysfunction of long-range connections within the frontal lobe in autism. The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such as autism in part through modulation of frontal lobe connectivity.

Fig. 1

Comparison between risk and nonrisk carriers of the autism-associated CNTNAP2 allele (rs2710102) during reward processing. (Top) Significantly reduced activation in mPFC in the nonrisk individuals compared to risk carriers (Z > 2.3, P < 0.05, after correction for multiple comparisons). The location of the seed region for subsequent analysis in the replication cohort is circled in green.

Fig. 2

Functional connectivity with the mPFC is associated with CNTNAP2. (A) Yellow circles highlight the discrete left-lateralized mPFC functional connectivity network observed in the nonrisk group, in contrast to the more distributed, bilateral network observed in the risk group. Lateral (columns 1 and 2) and medial (columns 3 and 4) views are displayed with left (L) and right (R) hemispheres indicated. Maps are corrected for multiple comparisons at the cluster level (Z >2.3, P <0.05).(B) A direct contrast between risk and nonrisk groups shows relatively greater long-range anterior-posterior connectivity in nonrisk versus risk carriers (blue arrow) and relatively greater right frontal connectivity in risk carriers compared to the nonrisk group (pink arrow). Discovery (row 1), replication (row 2), and combined cohort (row 3) analyses are illustrated separately. Maps are corrected for multiple comparisons at the cluster level (Z > 2.3, P <0.05).