Browsing by Author "Cheng, Rong"

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    Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals
    (American Medical Association, 2015-11) Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina; Department of Psychiatry, IU School of Medicine
    IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
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    Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease
    (Nature Publishing Group, 2014-09) Nalls, Mike A.; Pankratz, Nathan; Lill, Christina M.; Do, Chuong B.; Hernandez, Dena G.; Saad, Mohamad; DeStefano, Anita L.; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F.; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H.; Cheng, Rong; Ikram, M. Arfan; Ioannidis, John P. A.; Hadjigeorgiou, Georgios M.; Bis, Joshua C.; Martinez, Maria; Perlmutter, Joel S.; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H.; Clark, Lorraine N.; Stefansson, Kari; Hardy, John A.; Heutink, Peter; Chen, Honglei; Wood, Nicholas W.; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K.; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B.; Department of Medical & Molecular Genetics, IU School of Medicine
    We conducted a meta analysis of Parkinson’s disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as genome-wide significant
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    Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease
    (Elsevier, 2015-12) Barral, Sandra; Cheng, Rong; Reitz, Christiane; Vardarajan, Badri; Lee, Joseph; Kunkle, Brian; Beecham, Gary; Cantwell, Laura S.; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Haines, Jonathan L.; Goate, Alison M.; Foroud, Tatiana; Boerwinkle, Eric; Schellenberg, Gerard D.; Mayeux, Richard; Department of Medical and Molecular Genetics, IU School of Medicine
    INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.