Karen T. Cuenco

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid β peptide (Aβ) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

The impact of race as a risk factor for symptom severity and age at diagnosis of uterine leiomyomata among affected sisters.

OBJECTIVE The objective of the study was to identify risk factors for uterine leiomyomata (UL) in a racially diverse population of women with a family history of UL, and to evaluate their contribution to disease severity and age at diagnosis. STUDY DESIGN We collected and analyzed epidemiologic data from 285 sister pairs diagnosed with UL. Risk factors for UL-related outcomes were compared among black (n = 73) and white (n = 212) sister pairs using univariate and multivariate regression models. RESULTS Black women reported an average age at diagnosis of 5.3 years younger (SE, 1.1; P < .001) and were more likely to report severe disease (odds ratio, 5.22; 95% confidence interval, 1.99-13.7, P < .001) than white women of similar socioeconomic status. CONCLUSION Self-reported race is a significant factor in the severity of UL among women with a family history of UL. Differences in disease presentation between races likely reflect underlying genetic heterogeneity. The affected sister-pair study design can address both epidemiological and genetic hypotheses about UL.

Association of Distinct Variants in SORL1 With Cerebrovascular and Neurodegenerative Changes Related to Alzheimer Disease

BACKGROUND Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8-10 and 22-25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples. OBJECTIVE To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease. DESIGN, SETTING, AND PATIENTS We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study. We performed single- and 3-SNP haplotype association analyses using family-based tests. Haplotypes found to be significantly associated with at least 1 MRI trait were tested for association with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD. RESULTS In white patients, white matter hyperintensities were associated with multiple markers in the region encompassing SNPs 6 to 10, whereas cerebral and hippocampal atrophy were associated with markers from the region including SNPs 21 to 26. Examination of specific 3-SNP haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with SNPs 8 to 10 and association of hippocampal atrophy with SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was associated with fewer white matter changes in the clinical (P<.001) and autopsy (P=.02) samples. CONCLUSIONS Variants of SORL1 previously associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. These findings not only support the hypothesis that multiple areas in SORL1 are of functional importance but also raise the possibility that multiple SORL1 variants influence amyloid precursor protein or endothelial lipoprotein processing or both in different regions of the brain.

Heritability of magnetic resonance imaging (MRI) traits in Alzheimer disease cases and their siblings in the MIRAGE study

Magnetic resonance imaging (MRI) traits can serve as more specific measures of degenerative or cerebrovascular brain injury than can be ascertained through personal history, risk factors, clinical signs, or symptoms. They are potentially useful intermediate phenotypes for genetic studies of Alzheimer disease (AD). Recent studies have estimated heritability of white matter hyperintensity (WMH) among cognitively normal family members to be between 0.55 and 0.73. Persons discordant for AD are expected to have substantially different MRI phenotype distributions; our goal was to determine whether MRI traits in siblings discordant for AD are heritable. We measured cerebral atrophy, medial temporal atrophy (MTA), WMH, and a rating of cerebrovascular disease (CVR) via MRI in 815 participants from 424 families of the Multi-Institutional Research in Alzheimers Genetic Epidemiology Study. Residual heritability after adjustment for covariates ranged from 0.17 (P=0.009) for MTA to 0.57 (P=10−7) for CVR. The number of APOE-ϵ4 alleles was significantly associated with WMH (P=0.01) and CVR (P=0.005) but not cerebral atrophy (P=0.25) or MTA (P=0.83). Heritability remained significant and high after adjusting for APOE genotype, suggesting that a substantial proportion of the additive genetic variation in these MRI traits is explained by other genes. In the Multi-Institutional Research in Alzheimers Genetic Epidemiology Study of AD-discordant siblings, MRI traits are heritable and are potential endophenotypes for genetic association studies.

Magnetic Resonance Imaging Traits in Siblings Discordant for Alzheimer Disease

Magnetic resonance imaging (MRI) can aid clinical assessment of brain changes potentially correlated with Alzheimer disease (AD). MRI traits may improve our ability to identify genes associated with AD‐outcomes. We evaluated semi‐quantitative MRI measures as endophenotypes for genetic studies by assessing their association with AD in families from the Multi‐Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) Study.

Two-stage approach for identifying single-nucleotide polymorphisms associated with rheumatoid arthritis using random forests and Bayesian networks

We used the simulated data set from Genetic Analysis Workshop 15 Problem 3 to assess a two-stage approach for identifying single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA). In the first stage, we used random forests (RF) to screen large amounts of genetic data using the variable importance measure, which takes into account SNP interaction effects as well as main effects without requiring model specification. We used the simulated 9187 SNPs mimicking a 10 K SNP chip, along with covariates DR (the simulated DRB1 gentoype), smoking, and sex as input to the RF analyses with a training set consisting of 750 unrelated RA cases and 750 controls. We used an iterative RF screening procedure to identify a smaller set of variables for further analysis. In the second stage, we used the software program CaMML for producing Bayesian networks, and developed complex etiologic models for RA risk using the variables identified by our RF screening procedure. We evaluated the performance of this method using independent test data sets for up to 100 replicates.

Association of TTR polymorphisms with hippocampal atrophy in Alzheimer disease families

In vitro and animal model studies suggest that transthyretin (TTR) inhibits the production of the amyloid β protein, a major contributor to Alzheimer disease (AD) pathogenesis. We evaluated the association of 16 TTR single nucleotide polymorphisms (SNPs) with AD risk in 158 African American and 469 Caucasian discordant sibships from the MIRAGE Study. There was no evidence for association of TTR with AD in either population sample. To examine the possibility that TTR SNPs affect specific components of the AD process, we tested association of these SNPs with four measures of neurodegeneration and cerebrovascular disease defined by magnetic resonance imaging (MRI) in a subset of 48 African American and 265 Caucasian sibships. Five of seven common SNPs and several haplotypes were significantly associated with hippocampal atrophy in the Caucasian sample. Two of these SNPs also showed marginal evidence for association in the African American sample. Results for the other MRI traits were unremarkable. This study highlights the potential value of neuroimaging endophenotypes as a tool for finding genes influencing AD pathogenesis.

P1-283: Ethnic differences in MRI scans among Alzheimer’s disease patients and unaffected siblings in the MIRAGE Study

Karen T. Cuenco, Jingmei Zhang, Rodney CP Go, Robert P. Friedland, Ranjan Duara, Alexander Kurz, A. Dessa Sadovnick, Abi Akomolafe, for the MIRAGE Study, Helena Chui, Helen Petrovitch, Magda Tsolaki, Thomas O. Obisesan, Marwan N. Sabbagh, Martin Farlow, Norman R. Relkin, Kathyrn Lunetta, Adrienne Cupples, Robert C. Green, Lindsay A. Farrer, Charles DeCarli, Boston University School of Medicine, Boston, MA, USA; University of Alabama, Birmingham, AL, USA; Case Western Reserve University, Cleveland, OH, USA; University of Miami School of Medicine, Miami, FL, USA; The Technical University of Munich, Munich, Germany; University of British Columbia, Vancouver, BC, Canada; Morehouse School of Medicine, Atlanta, GA, USA; Rancho Los Amigos National Rehabilitation Center, University of Southern California, Downey, CA, USA; Pacific Health Research Institute, Honolulu, HI, USA; G. Papanicolaou Hospital, Thessaloniki, Greece; Howard University, Washington, DC, USA; Sun Health Research Institute, Sun City, AZ, USA; Indiana University School of Medicine, Indianapolis, IN, USA; Cornell Medical University, New York, NY, USA; Boston University School of Public Health, Boston, MA, USA; University of California at Davis, Sacramento, CA, USA. Contact e-mail: ktcuenco@bu.edu