Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression

Neurodegenerative Disease Caregivers' 5-HTTLPR Genotype Moderates the Effect of Patients' Empathic Accuracy Deficits on Caregivers' Well-Being.

ObjectiveTo test the hypothesis that a functional polymorphism of the serotonin transporter gene (serotonin-transporter-linked polymorphic region [5-HTTLPR]), which is thought to be associated with differential environmental sensitivity, moderates the association between low levels of empathic accuracy (i.e., ability to recognize emotions in others) in patients with neurodegenerative disease and caregivers' well-being.MethodsParticipants were 54 patients with neurodegenerative disease and their caregivers. Patients' empathic accuracy was measured using a dynamic tracking task in which they continuously rated the emotions of a character in a film; accuracy was determined by comparing patient ratings with those made by an expert panel. Caregivers provided a saliva sample for genotyping. Caregivers' well-being was measured as a latent construct indicated by validated measures of depression, anxiety, and negative affect.ResultsLower levels of patients' empathic accuracy were associated with lower levels of caregivers' well-being. Importantly, caregivers' 5-HTTLPR genotype moderated this association such that lower empathic accuracy in patients predicted lower well-being for caregivers with the short/short genotype (standardized β = 0.66), but not for caregivers with the short/long (standardized β = 0.05) or long/long genotypes (standardized β = -0.21).ConclusionConsistent with previous findings that the short/short variant of 5-HTTLPR is associated with greater sensitivity to environmental influences, caregivers with the short/short variant manifest lower well-being when caring for a patient with low levels of empathic accuracy than caregivers with the other variants. This finding contributes to the authors' understanding of biological factors associated with individual differences in caregiver vulnerability and resilience

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects

Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression