Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma

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.     

Living and Robotic Dogs as Elicitors of Social Communication Behavior and Regulated Emotional Responding in Individuals with Autism and Severe Language Delay: A Preliminary Comparative Study

The inclusion of animals and robots in therapeutic interventions for Autism Spectrum Disorder (ASD) has become more common. This study provides a first comparison between the potential of living versus robotic dogs to elicit social communication behavior and regulated emotional responses in individuals with ASD. Ten children and thirteen adults with ASD and severe lan- guage delay were tested for appropriate social communication behavior and cardiac autonomic functioning during a planned, structured interaction with an experimenter alone (no-stimulus condition), an experimenter accompanied by a living dog (dog condition), and an experimenter accompanied by a robotic dog (robot condition). A within-subjects design was followed to expose all participants to all three experimental conditions. Overall, participants (children and adults) showed a higher percentage of appropriate social behaviors in Living and Robotic Dogs as Elicitors of Social Communication Behavior and Regulated Emotional?…?the dog and the robot conditions than in the no-stimulus condition. In children, the living dog was more effective than the robotic dog in promoting social communication behavior. In adults, no such difference was found between the dog and the robot condition. Only the dog appeared to elicit a positive effect in cardiac autonomic functioning by increasing heart rate variability (HRV) and buffer- ing the decrease in parasympathetic activity due to interaction with the experimenter. The data are preliminary but relevant and warrant replication in larger-scale studies.