Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.
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.
Center for Cognitive Neuroscience, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Ashley A
AA
Scott-Van Zeeland
Brett S
BS
Abrahams
Ana I
AI
Alvarez-Retuerto
Lisa I
LI
Sonnenblick
Jeffrey D
JD
Rudie
Dara
D
Ghahremani
Jeanette A
JA
Mumford
Russell A
RA
Poldrack
Mirella
M
Dapretto
Daniel H
DH
Geschwind
Susan Y
SY
Bookheimer
D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D005625:Frontal Lobe / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009434:Neural Pathways; D012307:Risk Factors
C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins