To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

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A set of five clinical characteristics can be used in randomized studies to select lower back pain that will be well relieved by facet joint anesthesia. These characteristics should not, however, be considered as definite diagnostic criteria of lower back pain originating from facet joints.

D1Dimension 1 METHOD Three studies were performed. Two studies included only physiotherapy-treated patients, with 13 patients (males mean age 11y 7mo, SD 1y 10mo, range 8-14y) in the 3-month study and 41 patients (males mean age 14y 1mo, SD 5y 5mo, range 6-32y) in the 1-year study. A third study compared 12 patients treated with steroids with 12 age-and motor-function-matched untreated patients (males mean age of treated patients 10y 2mo, SD 2y 2mo range 6-14) over a 12-month period.RESULTS Over 3 months, the MFM D1 subscore (standing and transfers) decreased significantly ()4.7%; p<0.01). Over 1 year, all MFM subscores decreased significantly: )4.9% for D1 (p<0.01); )7.7% for D2 (axial and proximal motor capacity; p<0.01); )4.3% for D3 (distal motor capacity; p=0.03); and )5.8% for the total score (p<0.01). A threshold value for loss of ambulation and a predictive value 1 year before loss were estimated (total score 70% and D1 subscore 40%). Compared with the controls, patients treated with steroids had more stable total scores ()0.59 vs )5.87; p=0.02) and D2 subscores (0.98 vs )8.50; p<0.01).

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.MethodsWe conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.ResultsWe identified 5 associated loci at a genome-wide significance threshold P < 5 × 10− 8, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10− 6). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson’s disease and amyotrophic lateral sclerosis.ConclusionsIn total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0270-8) contains supplementary material, which is available to authorized users.

Aims: To investigate psychiatric disorders, somatic health, and professional effects in French train drivers having experienced a ''person under train'' accident, and somatic health and professional effects. Methods: A total of 202 train drivers were evaluated several times: immediately after the event, three months later, and one, two, and three years later. These drivers were compared with 186 train drivers not exposed to that psychotraumatic shock. The evaluations relied primarily on the GHQ-28 and MINI questionnaires. Results: In the exposed group, at the first evaluation, the prevalence of post-traumatic stress was 4%; scores >5 on the GHQ-28 were significantly higher than in the non-exposed group (32% versus 6%), for both the overall result and three sub-scores (somatic symptoms, anxiety and sleep, and psychosocial functioning). All these differences disappeared within a year. Vulnerability factors concerned prior traumas, acute and lasting life events, and the particular occupational situation where the driver is not accompanied but drives the train away alone in the aftermath of the accident. Over 95% of subjects had no short, medium, or long term impairment of their occupational fitness. Conclusions: Most of the psycho-behavioural disorders were observed in the immediate aftermath of the accident and disappeared within a year. The driver's occupational future does not seem to be affected by the ''person under train'' accident. Consideration of a traumatic accident as a job related risk and close psychological support of drivers after an accident probably increase the subject's ability to recover from the event.

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