Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation ...identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.
Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients.
The aim of this study was to ...assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk.
We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results.
Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001).
Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD.
•Smoking is associated with a lower mean age at PD onset.•In the overall PD cohort, APOE genotype was not associated with age at PD onset.•PD patients with an early onset (below 50 years) had an increased survival rate.
Sex plays a role in Parkinson's disease (PD) mechanisms. We analyzed sex difference manifestations among Spanish patients with PD.
PD patients who were recruited from the Spanish cohort COPPADIS from ...January 2016 to November 2017 were included. A cross-sectional and a two-year follow-up analysis were conducted. Univariate analyses and general linear model repeated measure were used.
At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) fit the criteria for analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between the groups in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24;
= 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11;
= 0.259). Symptoms such as depression (
< 0.0001), fatigue (
< 0.0001), and pain (
< 0.00001) were more frequent and/or severe in females, whereas other symptoms such as hypomimia (
< 0.0001), speech problems (
< 0.0001), rigidity (
< 0.0001), and hypersexuality (
< 0.0001) were more noted in males. Women received a lower levodopa equivalent daily dose (
= 0.002). Perception of quality of life was generally worse in females (PDQ-39,
= 0.002; EUROHIS-QOL8,
= 0.009). After the two-year follow-up, the NMS burden (Non-Motor Symptoms Scale total score) increased more significantly in males (
= 0.012) but the functional capacity (Schwab and England Activities of Daily Living Scale) was more impaired in females (
= 0.001).
The present study demonstrates that there are important sex differences in PD. Long-term prospective comparative studies are needed.
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