Schematic of the study design. Pooled-DNA sequencing was performed in a single DNA pool of 172 individuals to identify known pathogenic or novel functional variants by using Illumina HiSeq 2000. The SPLINTER software was used to call the variants. High-confident variants were selected for Sequenom genotyping. For those validated functional variants, follow-up genotyping was performed in large case-control series to infer and compare the frequencies. Segregation analysis was then performed to determine whether disease status segregates with risk alleles. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate the impact of novel GRN splice-site mutation on the changes of GRN plasma levels. GRN, progranulin; SPLINTER, short indel prediction by large deviation inference and nonlinear true frequency estimation by recursion.