IntroductionLate-onset Alzheimer's disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) [3][4][5][6][7][8] . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10 -7 ) indicating that additional rare variants remain to be identified. Main TextOur previous work identified 19 genome-wide significant common variant signals in addition to APOE 9 , that influence risk for LOAD. These signals, combined with 'subthreshold' common variant associations, account for ~31% of the genetic variance of LOAD 2 , leaving the majority of genetic risk uncharacterized 10 . To search for additional signals, we conducted a GWAS metaanalysis of non-Hispanic Whites (NHW) using a larger sample (17 new, 46 total datasets) from our group, the International Genomics of Alzheimer's Project (IGAP) (composed of four AD consortia: ADGC, CHARGE, EADI, and GERAD). This sample increases our previous discovery sample (Stage 1) by 29% for cases and 13% for controls (N=21,982 cases; 41,944 controls) ( Supplementary Table 1 and 2, and Supplementary Note). To sample both common and rare variants (minor allele frequency MAF ≥ 0.01, and MAF < 0.01, respectively), we imputed the discovery datasets using a 1000 Genomes reference panel consisting of . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a 11 36,648,992 single-nucleotide variants, 1,380,736 insertions/deletions, and 13,805 structural variants. After quality control, 9,456,058 common variants and 2,024,574 rare variants were selected for analysis (a 63% increase from our previous common variant analysis in 2013).Genotype dosages were analyzed within each dataset, and then combined with meta-analysis ( Supplementary Figures 1 and 2 and Supplementary Table 3). The Stage 1 discovery metaanalysis was first followed by Stage 2 using the I-select chip we previously developed in Lambert et al (including 11,632 variants, N=18,845) and finally stage 3A (N=6,998). The final sample was 33,692 clinical AD cases and 56,077 controls.Meta-analysis of Stages 1 and 2 produced 21 associations with P ≤ 5x10 -8 (Table 1 and Figure 1). Of these, 18 were previously reported as genome-wide significant and three of them are signals not initially described in Lambert et al: the rare R47H TREM2 coding va...

Significance Understanding loci nominated by genome-wide association studies (GWASs) is challenging. Here, we show, using the specific example of Parkinson disease, that identification of protein–protein interactions can help determine the most likely candidate for several GWAS loci. This result illustrates a significant general principle that will likely apply across multiple diseases.

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n = 1) or missense (n = 4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.

The authors examined the development over time of excessive daytime sleepiness (EDS) in patients with PD by evaluating EDS among 142 patients in 1993 and 4 years later. Eleven patients were diagnosed with EDS in 1993. In all of these patients, EDS persisted 4 years later. During followup, 30 new patients had EDS (6% new patients per year). In 1997, 29% of the patients with PD had EDS. The development of EDS correlated with more advanced disease and dementia.In patients with PD, various sleeping problems are reported to be more common than in the general population. 1,2 Both insomnia during the night and somnolence during the day are important sleep disturbances observed in PD. We previously have studied the nocturnal problems of PD and found that 60.3% of patients with PD reported insomnia, compared with 33% among a group of healthy elderly control subjects. 1 In another study of daytime somnolence, we found that severe somnolence, called excessive daytime sleepiness (EDS), was present in 15% of patients with PD compared with 1% of healthy elderly. 2 We describe the development over time of daytime somnolence and the clinical characteristics of patients that develop EDS during a 4-year period. Materials and methods. Study population.In a prevalence study of PD in the Stavanger area of western Norway on January 1, 1993, we found that the crude prevalence rate was 110.9 per 100,000 inhabitants 3 (i.e., 245 patients). Patient recruitment was based on hospital files and information from all general practitioners, nursing homes, district nurses, and health visitors in the study area.In the 1993 study, 239 of the 245 patients with PD in the Stavanger area could be evaluated for daytime somnolence and nocturnal sleeping problems. 1,2 Four years later, 142 of the 245 PD patients were re-examined for sleeping problems. Eighty-nine patients had died, 5 refused to participate, 7 were rediagnosed as not having idiopathic PD, and the data obtained from 2 were incomplete because of poor compliance.Study design. The same standardized examination and questionnaires were used in 1993 and 1997. The patients who were difficult to transport were examined at their nursing homes. A close family member or a daily caregiver was asked to attend the session for support and additional clinical and demographic information. Patients were evaluated with a clinical examination, rating scales of Parkinsonism (Hoehn & Yahr staging 4 and the Unified PD Rating Scale 5 [UPDRS]), diagnostic criteria for dementia (DSM III-R 6 ), and Mini-Mental State Examination 7 (MMSE). The motor part of the UPDRS was scored when the patient was in her/his best "on" state.For the evaluation of daytime somnolence and insomnia at night, the patients with PD completed a standardized questionnaire. Patients were asked whether they had a nighttime sleeping problem and what kind of sleeping problem. Use of sleeping pills implied insomnia. The questionnaire also evaluated the frequency and duration of sleeping periods during daytime. Daytime somnolence was classified in...