Anna C Cummings

Publications (5)20.57 Total impact

• Article: Evaluating power and type 1 error in large pedigree analyses of binary traits.

  Anna C Cummings, Eric Torstenson, Mary F Davis, Laura N D'Aoust, William K Scott, Margaret A Pericak-Vance, William S Bush, Jonathan L Haines
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  ABSTRACT: Studying population isolates with large, complex pedigrees has many advantages for discovering genetic susceptibility loci; however, statistical analyses can be computationally challenging. Allelic association tests need to be corrected for relatedness among study participants, and linkage analyses require subdividing and simplifying the pedigree structures. We have extended GenomeSIMLA to simulate SNP data in complex pedigree structures based on an Amish pedigree to generate the same structure and distribution of sampled individuals. We evaluated type 1 error rates when no disease SNP was simulated and power when disease SNPs with recessive, additive, and dominant modes of inheritance and odds ratios of 1.1, 1.5, 2.0, and 5.0 were simulated. We generated subpedigrees with a maximum bit-size of 24 using PedCut and performed two-point and multipoint linkage using Merlin. We also ran MQLS on the subpedigrees and unified pedigree. We saw no inflation of type 1 error when running MQLS on either the whole pedigrees or the sub-pedigrees, and we saw low type 1 error for two-point and multipoint linkage. Power was reduced when running MQLS on the subpedigrees versus the whole pedigree, and power was low for two-point and multipoint linkage analyses of the subpedigrees. These data suggest that MQLS has appropriate type 1 error rates in our Amish pedigree structure, and while type 1 error does not seem to be affected when dividing the pedigree prior to linkage analysis, power to detect linkage is diminished when the pedigree is divided.
  PLoS ONE 01/2013; 8(5):e62615. · 4.09 Impact Factor
• Article: Genome-wide association and linkage study in the amish detects a novel candidate late-onset Alzheimer disease gene.

  Anna C Cummings, Lan Jiang, Digna R Velez Edwards, Jacob L McCauley, Renee Laux, Lynne L McFarland, Denise Fuzzell, Clare Knebusch, Laura Caywood, Lori Reinhart-Mercer, Laura Nations, John R Gilbert, Ioanna Konidari, Michael Tramontana, Michael L Cuccaro, William K Scott, Margaret A Pericak-Vance, Jonathan L Haines
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  ABSTRACT: To identify novel late-onset Alzheimer disease (LOAD) risk genes, we have analysed Amish populations of Ohio and Indiana. We performed genome-wide SNP linkage and association studies on 798 individuals (109 with LOAD). We tested association using the Modified Quasi-Likelihood Score test and also performed two-point and multipoint linkage analyses. We found that LOAD was significantly associated with APOE (P= 9.0 × 10-6) in all our ascertainment regions except for the Adams County, Indiana, community (P= 0.55). Genome-wide, the most strongly associated SNP was rs12361953 (P= 7.92 × 10-7). A very strong, genome-wide significant multipoint peak [recessive heterogeneity multipoint LOD (HLOD) = 6.14, dominant HLOD = 6.05] was detected on 2p12. Three additional loci with multipoint HLOD scores >3 were detected on 3q26, 9q31 and 18p11. Converging linkage and association results, the most significantly associated SNP under the 2p12 peak was at rs2974151 (P= 1.29 × 10-4). This SNP is located in CTNNA2, which encodes catenin alpha 2, a neuronal-specific catenin known to have function in the developing brain. These results identify CTNNA2 as a novel candidate LOAD gene, and implicate three other regions of the genome as novel LOAD loci. These results underscore the utility of using family-based linkage and association analyses in isolated populations to identify novel loci for traits with complex genetic architecture.
  Annals of Human Genetics 09/2012; 76(5):342-51. · 2.57 Impact Factor
• Article: Linkage and association of successful aging to the 6q25 region in large Amish kindreds.

  Digna R Velez Edwards, John R Gilbert, James E Hicks, Jamie L Myers, Lan Jiang, Anna C Cummings, Shengru Guo, Paul J Gallins, Ioanna Konidari, Laura Caywood, Lori Reinhart-Mercer, Denise Fuzzell, Claire Knebusch, Renee Laux, Charles E Jackson, Margaret A Pericak-Vance, Jonathan L Haines, William K Scott
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  ABSTRACT: Successful aging (SA) is a multidimensional phenotype involving living to older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting polymorphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we examined 263 cognitively intact Amish individuals age 80 and older (74 SA and 189 "normally aged") all of whom are part of a single 13-generation pedigree. A genome-wide association study of 630,309 autosomal single nucleotide polymorphisms (SNPs) was performed and analyzed for linkage using multipoint analyses and for association using the modified quasi-likelihood score test. There was evidence for linkage on 6q25-27 near the fragile site FRA6E region with a dominant model maximum multipoint heterogeneity LOD score = 3.2. The 1-LOD-down support interval for this linkage contained one SNP for which there was regionally significant evidence of association (rs205990, p = 2.36 × 10(-5)). This marker survived interval-wide Bonferroni correction for multiple testing and was located between the genes QKI and PDE10A. Other areas of chromosome 6q25-q27 (including the FRA6E region) contained several SNPs associated with SA (minimum p = 2.89 × 10(-6)). These findings suggest potentially novel genes in the 6q25-q27 region linked and associated with SA in the Amish; however, these findings should be verified in an independent replication cohort.
  Age 07/2012; · 6.28 Impact Factor
• Article: Mitochondrial haplogroup X is associated with successful aging in the Amish.

  Monique D Courtenay, John R Gilbert, Lan Jiang, Anna C Cummings, Paul J Gallins, Laura Caywood, Lori Reinhart-Mercer, Denise Fuzzell, Claire Knebusch, Renee Laux, Jacob L McCauley, Charles E Jackson, Margaret A Pericak-Vance, Jonathan L Haines, William K Scott
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  ABSTRACT: Avoiding disease, maintaining physical and cognitive function, and continued social engagement in long-lived individuals describe successful aging (SA). Mitochondrial lineages described by patterns of common genetic variants ("haplogroups") have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on SA in an Amish community sample. Cognitively intact volunteers aged ≥80 years (n = 261) were enrolled in a door-to-door survey of Amish communities in Indiana and Ohio. Individuals scoring in the top third for lower extremity function, needing little assistance with self-care tasks, having no depression symptoms, and expressing high life satisfaction were considered SA (n = 74). The remainder (n = 187) were retained as controls. These individuals descend from 51 matrilines in a single 13-generation pedigree. Mitochondrial haplogroups were assigned using the ten mitochondrial single nucleotide polymorphisms (mtSNPs) defining the nine most common European haplogroups. An additional 17 mtSNPs from a genome-wide association panel were also investigated. Associations between haplogroups, mtSNPs, and SA were determined by logistic regression models accounting for sex, age, body mass index, and matriline via generalized estimating equations. SA cases were more likely to carry Haplogroup X (OR = 7.56, p = 0.0015), and less likely to carry Haplogroup J (OR = 0.40, p = 0.0003). Our results represent a novel association of Haplogroup X with SA and suggest that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults.
  Human Genetics 07/2011; 131(2):201-8. · 5.07 Impact Factor
• Article: A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

  Anna C Cummings, Stephen L Lee, Jacob L McCauley, Lan Jiang, Amy Crunk, Lynne L McFarland, Paul J Gallins, Denise Fuzzell, Clare Knebusch, Charles E Jackson, William K Scott, Margaret A Pericak-Vance, Jonathan L Haines
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  ABSTRACT: Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States. We performed tests for linkage and for association using a marker set of nearly 6000 single-nucleotide polymorphisms. Parametric multipoint linkage analysis generated a logarithm of the odds of linkage (LOD) score of 2.44 on chromosome 6 in the SYNE1 gene, approximately 8 Mbp from the PARK2 gene. In a different region on chromosome 6 (∼67 Mbp from PARK2) an association was found for rs4302647 (p < 4.0 × 10(-6) ), which is not within 300 kb of any gene. While the association exceeds Bonferroni correction, it may yet represent a false positive due to the small sample size and the low minor allele frequency. The minor allele frequency in affecteds is 0.07 compared to 0.01 in unaffecteds. Taken together, these results support involvement of loci on chromosome 6 in the genetic etiology of PD.
  Annals of Human Genetics 05/2011; 75(3):351-8. · 2.57 Impact Factor