Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder
Intellectual and Developmental Disabilities Research Center; Department of Pathology
Genetics | Mental Disorders | Molecular Genetics | Psychiatry | Psychiatry and Psychology
Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher's exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders.
DOI of Published Version
Ginns EI, Galdzicka M, Elston RC, Song YE, Paul SM, Egeland JA. Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder. Mol Psychiatry. 2014 Oct 14. doi: 10.1038/mp.2014.118. [Epub ahead of print] PubMed PMID: 25311364. Link to article on publisher's site
Ginns, Edward I.; Galdzicka, Marzena; Elston, R. C.; Song, Y. E.; Paul, S. M.; and Egeland, J. A., "Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder" (2014). Intellectual and Developmental Disabilities Research Center Publications and Presentations. 55.