Disease 2020, a new strategic framework for the NHGRI Sequencing Program, was introduced with the goal of leveraging recent advances in genomic technology and statistical methods for gene discovery to systematically define the genetic basis of human disease and maximize the impact of genomic medicine. In response to this initiative, the Large-Scale Sequencing and Analysis Centers including the Baylor College of Medicine Human Genome Sequencing Center (HGSC), were invited to propose demonstration projects known as Center Initiated Projects (CIPs). Two CIPs were designed in accordance with the emphasis of the common disease component of Disease 2020 on 1) leading causes of morbidity and mortality for which a significant proportion of the heritability is still unexplained, and 2) availability of appropriately consented DNA samples from individuals enrolled in large deeply phenotyped cohort studies; these CIPs are described below:
A.
More...Disease 2020, a new strategic framework for the NHGRI Sequencing Program, was introduced with the goal of leveraging recent advances in genomic technology and statistical methods for gene discovery to systematically define the genetic basis of human disease and maximize the impact of genomic medicine. In response to this initiative, the Large-Scale Sequencing and Analysis Centers including the Baylor College of Medicine Human Genome Sequencing Center (HGSC), were invited to propose demonstration projects known as Center Initiated Projects (CIPs). Two CIPs were designed in accordance with the emphasis of the common disease component of Disease 2020 on 1) leading causes of morbidity and mortality for which a significant proportion of the heritability is still unexplained, and 2) availability of appropriately consented DNA samples from individuals enrolled in large deeply phenotyped cohort studies; these CIPs are described below:
A. The Genetic Architecture of Common Chronic Disease
This study includes 4,000 participants from the population-based Atherosclerosis Risk in Communities (ARIC) Study with a focus on identification of rare and low frequency variants associated with cardiovascular disease and its risk factors by exome sequencing. Both African-Americans and European-Americans are included. At inception of the study in 1986-1989, 15,792 individuals aged 45 to 64 years were selected by probability sampling from 4 U.S. communities: Forsyth County, North Carolina; Minneapolis, Minnesota; Washington County, Maryland; and Jackson, Mississippi. Detailed demographic, clinical, and environmental variables have been collected during five examinations (exam 1, 1987-1989; exam 2, 1990-1992; exam 3, 1993-1995; exam 4, 1996-1998, and exam 5, 2011-2013), and subjects were contacted annually to update their medical histories. The phenotype data and substantial numbers of derived variables are already available via dbGAP. The study participants for this CIP can be considered a random sample of ARIC study participants with available DNA, and who provided written informed consent for genetic studies and data sharing. In addition, prior investment in sequencing and genotyping in the ARIC cohort will allow the data obtained from this CIP to be combined with other collaborative efforts including Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium (CHARGE-S), the NHLBI Grand Opportunity Exome Sequencing Project (GO-ESP), and Hypertension to create a well-powered study for multiple phenotypes consisting of approximately 11,000 persons. Replication and validation of study findings is sought through ARIC’s membership in established consortia such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
B. Rare and Common Variants Contribute to Age-Related Change in Brain Morphology and Cognitive Decline: ARIC
Alzheimer’s disease (AD) is the most common form of dementia, and is characterized by significant impairment in memory, behavioral changes, and gradual loss of autonomy. More than 5 million Americans 65 years or older are currently estimated to be affected with AD. The neuropathological features of AD are extracellular deposits of plaques composed of -amyloid peptides and intraneuronal neurofibrillary tangles containing hyperphosphorylated tau. A definitive diagnosis requires both a clinical assessment and examination at autopsy. Because individuals with dementia may have features of both vascular and AD pathology, and there is no biomarker that can be used to confirm the clinical diagnosis, genetic studies of AD can be complicated by phenotypic heterogeneity. Accordingly, genetic analysis of heritable endophenotypes, such as cognitive function and brain morphology that may be closer to the underlying disease pathophysiology and more directly related to gene expression, may help to uncover loci that increase susceptibility to AD before diagnostic criteria are met.
To evaluate the contribution of rare and low frequency coding variants to changes in cognition and brain morphology, exome sequencing was performed in 2,905 European-American participants from three cohort studies included in the CHARGE Consortium: the Atherosclerosis Risk in Communities (ARIC) Study (n= 15,792)), the Cardiovascular Health Study (CHS) (n = 5,888), and the Framingham Heart Study (FHS) (n = 14,428). Selection of study subjects was carried out within each of the three cohorts. During the first two years of the third ARIC examination (1993-1994), 966 European-American and 960 African-American participants aged 55 and older from the Forsyth County and Jackson field centers were invited to undergo cranial magnetic resonance imaging (MRI). Three validated neurocognitive tests chosen to represent different domains (Delayed Word Recall Test, verbal memory; Word Fluency Test, executive function; and Digit Symbol Substitution Test, processing speed) were administered to the entire cohort at the second and fourth ARIC clinic visits. In 2004-2006, 1,025 study participants underwent a second cerebral MRI examination and additional cognitive testing at the Forsyth and Jackson sites. Brain images were graded both semi-quantitatively (at visit 3 and at the Brain MRI follow-up visit) and quantitatively (follow-up visit only) for hippocampal volume. Thus, sequencing of the 966 European-American participants in the ARIC MRI study allows cross-sectional analysis of cerebral MRI measurements at visit 3, change in MRI variables between visit 3 and the Brain MRI follow-up visit, change in cognition between visits 2 and 4 (6-year change), and change in cognition between visit 2 and the Brain MRI follow-up visit (14-year change).
To fulfill the allocation of FHS samples for this CIP, 939 participants who had at least two MRI scans to assess hippocampal volume an average of six years apart and who had not had exome sequencing performed as part of other collaborative efforts such as CHARGE-S and GO-ESP were included. All FHS participants also had a 45 minute cognitive assessment at the same time as each MRI including a test of delayed recall (Logical Memory I adapted from the Original Wechsler Memory Scale). CHS used similar criteria so that 835 individuals with at least one MRI to evaluate hippocampal volume who had not been sequenced previously were selected. Among these CHS participants, 252 had hippocampal volume measured using a quantitative MRI scan, and 824 had data available for 6-year change in scores for the Digit Symbol Substitution Test. An additional group of 165 persons without hippocampal volume measurements but who had taken the Digit Symbol Substitution Test twice six years apart were also chosen for sequencing. Meta-analysis strategies can be used to combine results for the three CHARGE cohorts. All sequencing was carried out at the HGSC. This study contains the ARIC study subset of the CIP. Additional data from CHS and FHS is also available via dbGaP.
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