Functional mapping of disease susceptibility loci using cell biology.
In most genome-wide linkage studies, implication of a causative disease gene often requires years of expanding the study to more families and finer mapping of the initially described region. Even after such efforts, unobtainable sample sizes can be required to make statistically meaningful conclusions about a single gene. Here we demonstrate that by adding a layer of functional biology to statistical genetic results, this process can be accelerated. The diabetes susceptibility locus (chromosome 18p11) was systematically dissected by using a cell-based secretion assay and RNA interference, and we identified laminin alpha1 to have a role in pancreatic beta cell secretion. The screen was extended to identify laminin receptor 1 as a functional partner in regards to beta cell function. Our approach can potentially be widely used in the setting of high-throughput cellular screening of other loci to identify candidate genes.
The Judith P. Sulzberger, M.D., Columbia Genome Center and Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. peter.antinozzi@clocs.com
Peter A
PA
Antinozzi
Alejandro
A
Garcia-Diaz
Chuan
C
Hu
James E
JE
Rothman
D002460:Cell Line; D002874:Chromosome Mapping / Q000379:methods*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017474:Receptors, Laminin / Q000235:genetics / Q000502:physiology; D014162:Transfection
D007797:Laminin; D034741:RNA, Small Interfering; D017474:Receptors, Laminin; C084098:laminin A