Previously reported placebo-response-associated variants do not predict patient outcomes in inflammatory disease Phase III trial placebo arms.

In clinical trials, a placebo response refers to improvement in disease symptoms arising from the psychological effect of receiving a treatment rather than the actual treatment under investigation. Previous research has reported genomic variation associated with the likelihood of observing a placebo response, but these studies have been limited in scope and have not been validated. Here, we analyzed whole-genome sequencing data from 784 patients undergoing placebo treatment in Phase III Asthma or Rheumatoid Arthritis trials to assess the impact of previously reported variation on patient outcomes in the placebo arms and to identify novel variants associated with the placebo response. Contrary to expectations based on previous reports, we did not observe any statistically significant associations between genomic variants and placebo treatment outcome. Our findings suggest that the biological origin of the placebo response is complex and likely to be variable between disease areas.

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 beta peptide (Abeta) 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 Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Epigenetic influence of KAT6B and HDAC4 in the development of skeletal malocclusion.

INTRODUCTION: Genetic influences on the development of malocclusion include heritable effects on both masticatory muscles and jaw skeletal morphology. Beyond genetic variations, however, the characteristics of muscle and bone are also influenced by epigenetic mechanisms that produce differences in gene expression. We studied 2 enzymes known to change gene expressions through histone modifications, chromatin-modifying histone acetyltransferase KAT6B and deacetylase HDAC4, to determine their associations with musculoskeletal variations in jaw deformation malocclusions. METHODS: Samples of masseter muscle were obtained from subjects undergoing orthognathic surgery from 6 malocclusion classes based on skeletal sagittal and vertical dysplasia. The muscles were characterized for fiber type properties by immunohistochemistry, and their total RNA was isolated for gene expression studies by microarray analysis and quantitative real-time polymerase chain reaction. RESULTS: Gene expressions for fast isoforms of myosins and contractile regulatory proteins and for KAT6B and HDAC4 were severalfold greater in masseter muscles from a patient with a deepbite compared with one with an open bite, and genes related to exercise and activity did not differ substantially. In the total population, expressions of HDAC4 (P = 0.03) and KAT6B (P = 0.004) were significantly greater in subjects with sagittal Class III than in Class II malocclusion, whereas HDAC4 tended to correlate negatively with slow myosin type I and positively with fast myosin gene, especially type IIX. CONCLUSIONS: These data support other published reports of epigenetic regulation in the determination of skeletal muscle fiber phenotypes and bone growth. Further investigations are needed to elucidate how this regulatory model might apply to musculoskeletal development and malocclusion.

Genome-wide association scan of dental caries in the permanent dentition.

BACKGROUND: Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults. METHODS: Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries. RESULTS: Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens. CONCLUSIONS: As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.

Heritable factors play a major role in determining host responses to Wuchereria bancrofti infection in an isolated South Pacific island population.

BACKGROUND: It is increasingly recognized that host genetic factors may play an important role in determining the outcome of filarial infections. To test this hypothesis in bancroftian lymphatic filariasis, pedigree data were collected twice during an 18-year period from an isolated Polynesian population living on a Pacific island where lymphatic filariasis is endemic. METHODS: Using variance-component analysis, we examined the contribution of shared genetic and environmental effects on host clinical and immune responses to filarial infection, along with potential confounding determinants. RESULTS: Sex was found to have a negligible influence on heritability estimates, but shared-household effects accounted for up to 32% of host variability. After accounting for these shared-household effects, heritability estimates suggested that levels of microfilariae and circulating adult worm antigen, as well as host eosinophil and immunoglobulin G antibody responses to larval and adult worm antigens, were highly heritable (range of heritability estimates, 0.15-0.84). CONCLUSIONS: These data provide evidence of a key role for genetic factors in determining the host response to filarial infections in humans and emphasize the complexity of the relationships among the host, parasite, and environment.

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.

Measuring associations between the microbiota and repeated measures of continuous clinical variables using a lasso-penalized generalized linear mixed model.

BACKGROUND: Human microbiome studies in clinical settings generally focus on distinguishing the microbiota in health from that in disease at a specific point in time. However, microbiome samples may be associated with disease severity or continuous clinical health indicators that are often assessed at multiple time points. While the temporal data from clinical and microbiome samples may be informative, analysis of this type of data can be problematic for standard statistical methods. RESULTS: To identify associations between microbiota and continuous clinical variables measured repeatedly in two studies of the respiratory tract, we adapted a statistical method, the lasso-penalized generalized linear mixed model (LassoGLMM). LassoGLMM can screen for associated clinical variables, incorporate repeated measures of individuals, and address the large number of species found in the microbiome. As is common in microbiome studies, when the number of variables is an order of magnitude larger than the number of samples LassoGLMM can be imperfect in its variable selection. We overcome this limitation by adding a pre-screening step to reduce the number of variables evaluated in the model. We assessed the use of this adapted two-stage LassoGLMM for its ability to determine which microbes are associated with continuous repeated clinical measures.We found associations (retaining a non-zero coefficient in the LassoGLMM) between 10 laboratory measurements and 43 bacterial genera in the oral microbiota, and between 2 cytokines and 3 bacterial genera in the lung. We compared our associations with those identified by the Wilcoxon test after dichotomizing our outcomes and identified a non-significant trend towards differential abundance between high and low outcomes. Our two-step LassoGLMM explained more of the variance seen in the outcome of interest than other variants of the LassoGLMM method. CONCLUSIONS: We demonstrated a method that can account for the large number of genera detected in microbiome studies and repeated measures of clinical or longitudinal studies, allowing for the detection of strong associations between microbes and clinical measures. By incorporating the design strengths of repeated measurements and a prescreening step to aid variable selection, our two-step LassoGLMM will be a useful analytic method for investigating relationships between microbes and repeatedly measured continuous outcomes.

The pathogenesis of filarial lymphedema: is it the worm or is it the host?

Our understanding of the pathogenesis of filarial lymphedema, although evolving, is still limited. Recurrent bacterial infections play a major role in the progression of lymphedema to elephantiasis, but the host and parasite factors that trigger disease development are not known. Field studies in Haiti show that lymphedema and host responses to parasite antigens cluster in families, consistent with the hypothesis that host genes influence lymphedema susceptibility. The recent recognition that filarial parasites harbor the endosymbiotic bacteria, Wolbachia, also raises questions about the potential contribution of the inflammatory response to Wolbachia antigens to lymphedema development. In this review, we discuss potential risk factors for lymphedema and try to integrate these in a model of pathogenesis.

Assessment of families for excess risk of lymphedema of the leg in a lymphatic filariasis-endemic area.

The influence of host genes on the distribution of lymphedema due to lymphatic filariasis is unknown. To assess this, pedigree and disease information were collected from lymphedema patients in a lymphatic filariasis-endemic area. These patients were female, with an average age of approximately 40 years, who were enrolled between June 1995 and July 1999 in a lymphedema treatment clinic, and from the rural Haitian community served by the clinic. Interviews were conducted between September 1998 and December 1999. Families with multiple lymphedema cases were of similar size, with an average of 15 members, as those families with only a single lymphedema case. We determined whether families observed to have multiple lymphedema cases had a higher prevalence of lymphedema than expected when stratified population estimates and family size were considered. Lymphedema of the leg was excessive in 15 of 43 families with multiple lymphedema cases. The number of families demonstrating excess disease was significantly different than was expected based on population estimates of lymphedema prevalence (P = 0.026). Families with multiple cases of lymphedema were not significantly larger in family size than families with a single lymphedema cases. Twelve of the 15 families had a male with lymphedema, which influenced the interpretation of the results. The significance of these results is discussed.

A family study of lymphedema of the leg in a lymphatic filariasis-endemic area.

The risk of filarial lymphedema may not be equivalent for all members of filaria-exposed populations. While evidence for a genetic factor that influences acquisition of infection has been growing, very little work has addressed whether there is a genetic basis to the development of disease due to lymphatic filariasis. We designed a family study of lymphedema in a rural community in Haiti to assess disease aggregation. Three hundred sixty-eight female patients sixteen years of age or older were enrolled at a lymphedema treatment clinic between June 1995 and December 1999. After applying additional eligibility criteria, 172 probands were enrolled into the family study for detailed pedigree collection between September 1998 and December 1999. Fifty-three lymphedema cases were identified among the probands' parents, full-siblings, children, half-siblings, and mating partners of the parents. Twelve of the 53 cases were among males. The proportion of cases occurring in a biologic parent of the proband was higher than in unrelated individuals married into the proband's family (P = 0.0010). This is the first large family study based on pedigrees to assess the familial aggregation of lymphedema due to filariasis. This family study will be useful to investigate the role of genes and environment in the development of filarial-related lymphedema.

Genome-wide association study of periodontal health measured by probing depth in adults ages 18-49 years.

The etiology of chronic periodontitis clearly includes a heritable component. Our purpose was to perform a small exploratory genome-wide association study in adults ages 18-49 years to nominate genes associated with periodontal disease-related phenotypes for future consideration. Full-mouth periodontal pocket depth probing was performed on participants (N = 673), with affected status defined as two or more sextants with probing depths of 5.5 mm or greater. Two variations of this phenotype that differed in how missing teeth were treated were used in analysis. More than 1.2 million genetic markers across the genome were genotyped or imputed and tested for genetic association. We identified ten suggestive loci (p-value ≤ 1E-5), including genes/loci that have been previously implicated in chronic periodontitis: LAMA2, HAS2, CDH2, ESR1, and the genomic region on chromosome 14q21-22 between SOS2 and NIN. Moreover, we nominated novel loci not previously implicated in chronic periodontitis or related pathways, including the regions 3p22 near OSBPL10 (a lipid receptor implicated in hyperlipidemia), 4p15 near HSP90AB2P (a heat shock pseudogene), 11p15 near GVINP1 (a GTPase pseudogene), 14q31 near SEL1L (an intracellular transporter), and 18q12 in FHOD3 (an actin cytoskeleton regulator). Replication of these results in additional samples is needed. This is one of the first research efforts to identify genetic polymorphisms associated with chronic periodontitis-related phenotypes by the genome-wide association study approach. Though small, efforts such this are needed in order to nominate novel genes and generate new hypotheses for exploration and testing in future studies.

Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G0-phase human cells.

We recently reported that homologous chromosomes make contact at the sites of double-strand breaks (DSBs) induced by ionizing radiation (IR) and the restriction endonuclease I-PpoI in G0/G1-phase somatic human cells. The contact involves short segments of homologous chromosomes and is centered on a DSB that occurs in a gene; contact does not occur at a DSB in intergenic DNA. Contact between homologous chromosomes is abrogated by inhibition of transcription and requires the kinase activity of ATM, but not DNA-PK. Here, we report additional insights into the mechanism underlying this novel phenomenon. We identify four patterns of homologous chromosome contact, and show that contact between homologous arms, but not centrosomes, is induced by IR. Significantly, we demonstrate that contact is induced by IR in non-proliferating, G0-phase human cells derived from tissue explants. Finally, we show that contact between homologous chromosomes is detectable as early as 5 min after IR. These results point to the existence of a mechanism that rapidly localizes homologous chromosome arms at sites of DSBs in genes in G0-phase human cells.

Multi-dimensional prioritization of dental caries candidate genes and its enriched dense network modules.

A number of genetic studies have suggested numerous susceptibility genes for dental caries over the past decade with few definite conclusions. The rapid accumulation of relevant information, along with the complex architecture of the disease, provides a challenging but also unique opportunity to review and integrate the heterogeneous data for follow-up validation and exploration. In this study, we collected and curated candidate genes from four major categories: association studies, linkage scans, gene expression analyses, and literature mining. Candidate genes were prioritized according to the magnitude of evidence related to dental caries. We then searched for dense modules enriched with the prioritized candidate genes through their protein-protein interactions (PPIs). We identified 23 modules comprising of 53 genes. Functional analyses of these 53 genes revealed three major clusters: cytokine network relevant genes, matrix metalloproteinases (MMPs) family, and transforming growth factor-beta (TGF-ß) family, all of which have been previously implicated to play important roles in tooth development and carious lesions. Through our extensive data collection and an integrative application of gene prioritization and PPI network analyses, we built a dental caries-specific sub-network for the first time. Our study provided insights into the molecular mechanisms underlying dental caries. The framework we proposed in this work can be applied to other complex diseases.

Association signals unveiled by a comprehensive gene set enrichment analysis of dental caries genome-wide association studies.

Gene set-based analysis of genome-wide association study (GWAS) data has recently emerged as a useful approach to examine the joint effects of multiple risk loci in complex human diseases or phenotypes. Dental caries is a common, chronic, and complex disease leading to a decrease in quality of life worldwide. In this study, we applied the approaches of gene set enrichment analysis to a major dental caries GWAS dataset, which consists of 537 cases and 605 controls. Using four complementary gene set analysis methods, we analyzed 1331 Gene Ontology (GO) terms collected from the Molecular Signatures Database (MSigDB). Setting false discovery rate (FDR) threshold as 0.05, we identified 13 significantly associated GO terms. Additionally, 17 terms were further included as marginally associated because they were top ranked by each method, although their FDR is higher than 0.05. In total, we identified 30 promising GO terms, including 'Sphingoid metabolic process,' 'Ubiquitin protein ligase activity,' 'Regulation of cytokine secretion,' and 'Ceramide metabolic process.' These GO terms encompass broad functions that potentially interact and contribute to the oral immune response related to caries development, which have not been reported in the standard single marker based analysis. Collectively, our gene set enrichment analysis provided complementary insights into the molecular mechanisms and polygenic interactions in dental caries, revealing promising association signals that could not be detected through single marker analysis of GWAS data.

Demographic, socioeconomic, and behavioral factors affecting patterns of tooth decay in the permanent dentition: principal components and factor analyses.

OBJECTIVES: Dental caries of the permanent dentition is a multifactorial disease resulting from the complex interplay of endogenous and environmental risk factors. The disease is not easily quantitated due to the innumerable possible combinations of carious lesions across individual tooth surfaces of the permanent dentition. Global measures of decay, such as the DMFS index (which was developed for surveillance applications), may not be optimal for studying the epidemiology of dental caries because they ignore the distinct patterns of decay across the dentition. We hypothesize that specific risk factors may manifest their effects on specific tooth surfaces leading to patterns of decay that can be identified and studied. In this study, we utilized two statistical methods of extracting patterns of decay from surface-level caries data to create novel phenotypes with which to study the risk factors affecting dental caries. METHODS: Intra-oral dental examinations were performed on 1068 participants aged 18-75 years to assess dental caries. The 128 tooth surfaces of the permanent dentition were scored as carious or not and used as input for principal components analysis (PCA) and factor analysis (FA), two methods of identifying underlying patterns without a priori knowledge of the patterns. Demographic (age, sex, birth year, race/ethnicity, and educational attainment), anthropometric (height, body mass index, waist circumference), endogenous (saliva flow), and environmental (tooth brushing frequency, home water source, and home water fluoride) risk factors were tested for association with the caries patterns identified by PCA and FA, as well as DMFS, for comparison. The ten strongest patterns (i.e. those that explain the most variation in the data set) extracted by PCA and FA were considered. RESULTS: The three strongest patterns identified by PCA reflected (i) global extent of decay (i.e. comparable to DMFS index), (ii) pit and fissure surface caries and (iii) smooth surface caries, respectively. The two strongest patterns identified by FA corresponded to (i) pit and fissure surface caries and (ii) maxillary incisor caries. Age and birth year were significantly associated with several patterns of decay, including global decay/DMFS index. Sex, race, educational attainment, and tooth brushing were each associated with specific patterns of decay, but not with global decay/DMFS index. CONCLUSIONS: Taken together, these results support the notion that caries experience is separable into patterns attributable to distinct risk factors. This study demonstrates the utility of such novel caries patterns as new outcomes for exploring the complex, multifactorial nature of dental caries.

Association of maternal CNVs in GSTT1/GSTT2 with smoking, preterm delivery, and low birth weight.

Preterm delivery (PTD) is an adverse birth outcome associated with increased infant mortality and negative lifelong health consequences. PTD may be the result of interactions between genetics and maternal/fetal environmental factors including smoking exposure (SMK). A common deletion in the GSTT1 gene was previously reported to affect birth outcomes in smokers. In this study, we dissect the associations among SMK, birth outcomes, and copy number variations (CNVs) in the GSTT1/GSTT2 region. A preterm birth case-control dataset of 1937 mothers was part of the GENEVA preterm birth study, which included genome-wide genotyping used to identify CNVs. We examined the association of SMK with birth outcomes, detected CNVs within the GSTT1/GSTT2 region using PennCNV, and examined associations of the identified CNVs with preterm birth and with birth weight (BW) in full term birth controls, including interactions with SMK. Finally, we tested the association of CNVs in GSTT1/GSTT2 with SMK. We confirmed the association of smoking with low BW and PTD. We identified 2 CNVs in GSTT2 (GSTT2 (a) and GSTT2 (b) ), 1 CNV in GSTTP1 and 2 CNVs in GSTT1 (GSTT1 (a) and GSTT1 (b) ). The GSTT2 (a) deletion was associated with reduced BW (-284 g, p = 2.50E-7) in smokers, and was more common in smokers [odds ratio(OR) = 1.30, p = 0.04]. We found that the size of the reported common deletion CNV in GSTT1 was larger than previously shown. The GSTTP1 and GSTT1 (b) null genotypes were in high linkage disequilibrium (LD) (D' = 0.89) and less common in smokers (OR = 0.68, p = 0.019 and OR = 0.73, p = 0.055, respectively). These two deletions were in partial LD with GSTT2 (a) and GSTT2 (b) duplications. All 5 CNVs seem to be associated with increased risk of preterm birth before 35 completed weeks. CNVs in the GSTTT1/GSTT2 region appear associated with low BW and PTD outcomes, but LD complicated these CNVs in GSTT1/GSTT2. In genetic association studies of BW, multiple CNVs in this region need to be investigated instead of a single polymorphism.

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 ß 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.

The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. METHODS/PRINCIPAL FINDINGS: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). CONCLUSIONS/SIGNIFICANCE: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.

Magnetic resonance imaging traits in siblings discordant for Alzheimer disease.

BACKGROUND: 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. METHODS: Discordant siblings from multiple ethnicities were ascertained through a single affected proband. Semi-quantitative MRI measures were obtained for each individual. The association between continuous/ordinal MRI traits and AD were analyzed using generalized estimating equations. Medical history and Apolipoprotein E (APOE)epsilon4 status were evaluated as potential confounders. RESULTS: Comparisons of 214 affected and 234 unaffected subjects from 229 sibships revealed that general cerebral atrophy, white matter hyperintensities (WMH), and mediotemporal atrophy differed significantly between groups (each at P < .0001) and varied by ethnicity. Age at MRI and duration of AD confounded all associations between AD and MRI traits. Among unaffected sibs, the presence of at least one APOEepsilon4 allele and MRI infarction was associated with more WMH after adjusting for age at MRI. CONCLUSION: The strong association between MRI traits and AD suggests that MRI traits may be informative endophenotypes for basic and clinical studies of AD. In particular, WMH may be a marker of vascular disease that contributes to AD pathogenesis.