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...

Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the same genes harbour other, more common variants, which might have a lower penetrance and/or cause mild disease, perhaps indistinguishable from sporadic disease and accounting for a considerable proportion of the unexplained inherited risk of tumours in the general population. Germline variants at the APC locus are excellent candidates for explaining why some individuals are predisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients with 'multiple' (3-100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to three Ashkenazi patients with I1307K, we found seven patients with the E1317Q variant. E1317Q is significantly associated with multiple colorectal adenomas (OR = 11. 17, 95% CI = 2.30-54.3, p < 0.001), accounting for approximately 4% of all patients with multiple colorectal adenomas. In addition, four patients with truncating APC variants in exon 9 or in the 3' part of the gene were identified. Germline APC variants account for approximately 10% of patients with multiple adenomas. Unidentified predisposition genes almost certainly exist. We argue that it is worthwhile to screen multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.

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This study reports the first gene mapping of Native American myopathy (NAM) using single-nucleotide polymorphism-based homozygosity mapping in only a few affected individuals from simplex families and identified a novel NAM locus. Identifying the genetic basis of NAM may suggest new genetic etiologies for other more common conditions such as congenital myopathy and malignant hyperthermia.