Denise Fuzzell

Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene

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.

Rare complement factor H variant associated with age-related macular degeneration in the Amish

PURPOSE Age-related macular degeneration is the leading cause of blindness among the adult population in the developed world. To further the understanding of this disease, we have studied the genetically isolated Amish population of Ohio and Indiana. METHODS Cumulative genetic risk scores were calculated using the 19 known allelic associations. Exome sequencing was performed in three members of a small Amish family with AMD who lacked the common risk alleles in complement factor H (CFH) and ARMS2/HTRA1. Follow-up genotyping and association analysis was performed in a cohort of 973 Amish individuals, including 95 with self-reported AMD. RESULTS The cumulative genetic risk score analysis generated a mean genetic risk score of 1.12 (95% confidence interval [CI]: 1.10, 1.13) in the Amish controls and 1.18 (95% CI: 1.13, 1.22) in the Amish cases. This mean difference in genetic risk scores is statistically significant (P = 0.0042). Exome sequencing identified a rare variant (P503A) in CFH. Association analysis in the remainder of the Amish sample revealed that the P503A variant is significantly associated with AMD (P = 9.27 × 10(-13)). Variant P503A was absent when evaluated in a cohort of 791 elderly non-Amish controls, and 1456 non-Amish cases. CONCLUSIONS Data from the cumulative genetic risk score analysis suggests that the variants reported by the AMDGene consortium account for a smaller genetic burden of disease in the Amish compared with the non-Amish Caucasian population. Using exome sequencing data, we identified a novel missense mutation that is shared among a densely affected nuclear Amish family and located in a gene that has been previously implicated in AMD risk.

Linkage and association of successful aging to the 6q25 region in large Amish kindreds

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.

A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

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.

Examination of Candidate Exonic Variants for Association to Alzheimer Disease in the Amish

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.

Sequence analysis of CTNNA2 and LRRTM1 for late-onset Alzheimer's disease in the Amish

Broeckhoven, Philippe Amouyel, Diederik Moechars, Bart Dermaut, Jean-Charles Lambert, INSERM U744 Institut Pasteur de Lille, Lille, France; VIB-Laboratory of Behavioral and Developmental Genetics, Center of Human Genetics, Leuven, Belgium; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB and Institute Born-Bun, Antwerpen, Belgium; University of Antwerp, Antwerpen, Belgium; CNS Discovery, Beerse, Belgium.

THE GENETIC ARCHITECTURE OF ALZHEIMER DISEASE IN THE MID-WESTERN U.S. AMISH

JL Haines1,2, LN D’Aoust3, R Laux1, D Fuzzell1, L Caywood4, L Reinhart-Mercer4, WK Scott4, MA Pericak-Vance4 1Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH, USA 2Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA 3Vanderbilt University School of Medicine, Nashville, TN, USA 4Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA

Genome-wide study for Alzheimer’s disease in the Amish

tidepressants and cognitive behavior therapy)? 4)MBI has been shown to be risk factor for cognitive decline. SSRI treatment is associated with less AD pathology and cognitive deficits in transgenic AD mouse models. These observations underscore of importance of early interventions for DS and for human clinical and neurobiological studies to evaluate the effects of such interventions in the early course. Conclusions: An integrated, translational research agenda will be presented to address these important issues.