Neha Raghavan1,2,3, Giuseppe Tosto4,5,6. 1. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 622 W. 168th Street PH 19-314, New York, NY, 10032, USA. 2. Department of Neurology, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY, 10032, USA. 3. Institute for Genomic Medicine, Columbia University, New York, NY, 10032, USA. 4. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 622 W. 168th Street PH 19-314, New York, NY, 10032, USA. gt2260@cumc.columbia.edu. 5. Department of Neurology, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY, 10032, USA. gt2260@cumc.columbia.edu. 6. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 622 W. 168th Street PH 19-314, New York, NY, 10032, USA. gt2260@cumc.columbia.edu.
Abstract
PURPOSE OF REVIEW: We aimed to summarize the recent advances in genetic findings of Alzheimer's disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components. RECENT FINDINGS: Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components. We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.
PURPOSE OF REVIEW: We aimed to summarize the recent advances in genetic findings of Alzheimer's disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components. RECENT FINDINGS: Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components. We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.
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