Frontotemporal dementia and its subtypes: a genome-wide association study

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 7 10-8) single-nucleotide polymorphisms. Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 7 10-8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1\ub705 7 10-8; odds ratio=1\ub7204 [95% CI 1\ub711-1\ub730]), rs9268856 (p=5\ub751 7 10-9; 0\ub7809 [0\ub776-0\ub786]) and rs1980493 (p value=1\ub757 7 10-8, 0\ub7775 [0\ub769-0\ub786]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2\ub744 7 10-7; 0\ub7814 [0\ub771-0\ub792]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD

Review of the history and development in the field of psychosocial oncology

Psychosocial oncology is a multi-disciplinary field of practice and, as a recently developed speciality, covers the psychological, social and behavioural dimensions of cancer. We describe the historical background and changing ethos in medical practice in order to understand factors that contributed to the emergence of this new discipline. Modern psychosocial oncology covers a number of topics; the diagnosis and management of psychological morbidity and distress across the cancer continuum from diagnosis through survivorship and, for some patients, terminal illness, the recognition that behaviour and lifestyle contribute to cancer risk and prognosis, the need to include families and carers alongside patients in a comprehensive model of supportive cancer care. Best practice, based on evidence and nationally and internationally accepted guidelines, is being integrated into national cancer plans, and services are briefly described. Future challenges include the need to recognize that the behavioural and mental health sciences have a role to play in comprehensive cancer care and that multi-disciplinary care, which includes psychosocial care, is the best model for ensuring patients needs are comprehensively and adequately met. The return of modern medicine to a more holistic person-focused ethos is needed in order to put the patient back into patient-centred cancer care.No Full Tex

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population