title: Examination of candidate exonic variants for association to Alzheimer disease in the Amish.
abstract: Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome heterogeneity limitations associated with complex population studies. We determined that Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a dataset of unrelated individuals. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and from linkage regions implicated previous studies in the full dataset, new associations could be confirmed. The most significant result (p = 0.0012) was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18. However, this association is specific to the Amish and did not generalize when tested in a dataset of unrelated individuals. These results suggest that additional risk variation in the Amish remains to be identified and likely resides outside of the classical protein coding gene regions.
authors: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America.
authors: Laura N
authors: LN
authors: D'Aoust
authors: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America.
authors: Anna C
authors: AC
authors: Cummings
authors: Department of Epidemiology & Biostatistics and Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, United States of America.
authors: Renee
authors: R
authors: Laux
authors: Department of Epidemiology & Biostatistics and Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, United States of America.
authors: Denise
authors: D
authors: Fuzzell
authors: Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33101, United States of America.
authors: Laura
authors: L
authors: Caywood
authors: Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33101, United States of America.
authors: Lori
authors: L
authors: Reinhart-Mercer
authors: Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33101, United States of America.
authors: William K
authors: WK
authors: Scott
authors: Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33101, United States of America.
authors: Margaret A
authors: MA
authors: Pericak-Vance
authors: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America; Department of Epidemiology & Biostatistics and Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, United States of America.
authors: Jonathan L
authors: JL
authors: Haines
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D061365:Amish / Q000235:genetics*; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010641:Phenotype