title: Alzheimer's disease: rare variants with large effect sizes.
abstract: Recent advances in sequencing technology and novel genotyping arrays (focused on low-frequency and coding variants) have made it possible to identify novel coding variants with large effect sizes and also novel genes (TREM2, PLD3, UNC5C, and AKAP9) associated with Alzheimer's disease (AD) risk. The major advantages of these studies over the classic genome-wide association studies (GWAS) include the identification of the functional variant and the gene-driven association. In addition to the large effect size, these studies make it possible to model these variants and genes using cell and animal systems. On the other hand, the underlying population-variability of these very low allele frequency variants poses a great challenge to replicating results. Studies that include very large datasets (>10,000 cases and controls) and combine sequencing and genotyping approaches will lead to the identification of novel genes for Alzheimer's disease.
authors: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
authors: Jorge L
authors: JL
authors: Del-Aguila
authors: The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors: Daniel C
authors: DC
authors: Koboldt
authors: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
authors: Kathleen
authors: K
authors: Black
authors: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
authors: Rachel
authors: R
authors: Chasse
authors: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA.
authors: Joanne
authors: J
authors: Norton
authors: The Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors: Richard K
authors: RK
authors: Wilson
authors: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders. Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO 63110, USA. Electronic address: cruchagc@wustl.edu.
authors: Carlos
authors: C
authors: Cruchaga
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide