TY - JOUR
T1 - Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma
AU - Carrasquillo, Minerva M.
AU - Nicholson, Alexandra M.
AU - Finch, Nicole
AU - Gibbs, J. Raphael
AU - Baker, Matt
AU - Rutherford, Nicola J.
AU - Hunter, Talisha A.
AU - Dejesus-Hernandez, Mariely
AU - Bisceglio, Gina D.
AU - MacKenzie, Ian R.
AU - Singleton, Andrew
AU - Cookson, Mark R.
AU - Crook, Julia E.
AU - Dillman, Allissa
AU - Hernandez, Dena
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Younkin, Steven G.
AU - Rademakers, Rosa
N1 - Funding Information:
The authors wish to acknowledge and thank the families who contributed samples that were critically important to this study. This work was supported by the National Institutes of Health (grant numbers P50 AG16574 [Mayo Alzheimer's Disease Research Center, R.C.P. as PI; to R.R., N.R.G.-R., and S.G.Y.], U01 AG06576 [Mayo Alzheimer's Disease Patient Registry: R.C.P. as PI], R01 NS065782 [to R.R.], and R01 AG18023 [to N.R.G.-R. and S.G.Y.]).This project was also generously supported by the Consortium for Frontotemporal Dementia Research (to R.R.), the Robert and Clarice Smith Postdoctoral Fellowship (to M.M.C.), the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (to R.C.P., N.R.G.-R., and S.G.Y.), and the Palumbo Professorship in Alzheimer's Disease Research (to S.G.Y.). I.R.M. was supported by the Canadian Institutes of Health Research Operating (#74580) and the Pacific Alzheimer's Disease Research Foundation. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number ZIA AG000932-03.
PY - 2010/12/10
Y1 - 2010/12/10
N2 - Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Using an enzyme-linked immunosorbent assay, we previously showed that GRN is detectable in human plasma and can be used to predict GRN mutation status. This study also showed a wide range in plasma GRN levels in non-GRN mutation carriers, including controls. We have now performed a genome-wide association study of 313,504 single-nucleotide polymorphisms (SNPs) in 533 control samples and identified on chromosome 1p13.3 two SNPs with genome-wide significant association with plasma GRN levels (top SNP rs646776; p = 1.7 × 10-30). The association of rs646776 with plasma GRN levels was replicated in two independent series of 508 controls (p = 1.9 × 10-19) and 197 FTLD patients (p = 6.4 × 10-12). Overall, each copy of the minor C allele decreased GRN levels by ∼15%. SNP rs646776 is located near sortilin (SORT1), and the minor C allele of rs646776 was previously associated with increased SORT1 mRNA levels. Supporting these findings, overexpression of SORT1 in cultured HeLa cells dramatically reduced GRN levels in the conditioned media, whereas knockdown of SORT1 increased extracellular GRN levels. In summary, we identified significant association of a locus on chromosome 1p13.3 with plasma GRN levels through an unbiased genome-wide screening approach and implicated SORT1 as an important regulator of GRN levels. This finding opens avenues for future research into GRN biology and the pathophysiology of neurodegenerative diseases.
AB - Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Using an enzyme-linked immunosorbent assay, we previously showed that GRN is detectable in human plasma and can be used to predict GRN mutation status. This study also showed a wide range in plasma GRN levels in non-GRN mutation carriers, including controls. We have now performed a genome-wide association study of 313,504 single-nucleotide polymorphisms (SNPs) in 533 control samples and identified on chromosome 1p13.3 two SNPs with genome-wide significant association with plasma GRN levels (top SNP rs646776; p = 1.7 × 10-30). The association of rs646776 with plasma GRN levels was replicated in two independent series of 508 controls (p = 1.9 × 10-19) and 197 FTLD patients (p = 6.4 × 10-12). Overall, each copy of the minor C allele decreased GRN levels by ∼15%. SNP rs646776 is located near sortilin (SORT1), and the minor C allele of rs646776 was previously associated with increased SORT1 mRNA levels. Supporting these findings, overexpression of SORT1 in cultured HeLa cells dramatically reduced GRN levels in the conditioned media, whereas knockdown of SORT1 increased extracellular GRN levels. In summary, we identified significant association of a locus on chromosome 1p13.3 with plasma GRN levels through an unbiased genome-wide screening approach and implicated SORT1 as an important regulator of GRN levels. This finding opens avenues for future research into GRN biology and the pathophysiology of neurodegenerative diseases.
UR - http://www.scopus.com/inward/record.url?scp=78649796276&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649796276&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2010.11.002
DO - 10.1016/j.ajhg.2010.11.002
M3 - Article
C2 - 21087763
AN - SCOPUS:78649796276
SN - 0002-9297
VL - 87
SP - 890
EP - 897
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -