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Whole genome sequence analyses of brain imaging measures in the Framingham Study.

ABSTRACT: OBJECTIVE:We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. METHODS:We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants. RESULTS:We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways. CONCLUSIONS:Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

SUBMITTER: Sarnowski C

PROVIDER: S-EPMC5772158 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pulmonary function measures obtained by spirometry are used to diagnose chronic obstructive pulmonary disease (COPD) and are highly heritable. We conducted genome-wide association (GWA) analyses (Affymetrix 100K SNP GeneChip) for measures of lung function in the Framingham Heart Study.Ten spirometry phenotypes including percent of predicted measures, mean spirometry measures over two examinations, and rates of change based on forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow from the 25th to 75th percentile (FEF25-75), the FEV1/FVC ratio, and the FEF25-75/FVC ratio were examined. Percent predicted phenotypes were created using each participant's latest exam with spirometry. Predicted lung function was estimated using models defined in the set of healthy never-smokers, and standardized residuals of percent predicted measures were created adjusting for smoking status, pack-years, and body mass index (BMI). All modeling was performed stratified by sex and cohort. Mean spirometry phenotypes were created using data from two examinations and adjusting for age, BMI, height, smoking and pack-years. Change in pulmonary function over time was studied using two to four examinations with spirometry to calculate slopes, which were then adjusted for age, height, smoking and pack-years.Analyses were restricted to 70,987 autosomal SNPs with minor allele frequency > or = 10%, genotype call rate > or = 80%, and Hardy-Weinberg equilibrium p-value > or = 0.001. A SNP in the interleukin 6 receptor (IL6R) on chromosome 1 was among the best results for percent predicted FEF25-75. A non-synonymous coding SNP in glutathione S-transferase omega 2 (GSTO2) on chromosome 10 had top-ranked results studying the mean FEV1 and FVC measurements from two examinations. SNPs nearby the SOD3 and vitamin D binding protein genes, candidate genes for COPD, exhibited association to percent predicted phenotypes.GSTO2 and IL6R are credible candidate genes for association to pulmonary function identified by GWA. These and other observed associations warrant replication studies. This resource of GWA results for pulmonary function measures is publicly available at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.

Project description:BACKGROUND:Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. METHODS:A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999-2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency > or = 0.10, genotypic call rate > or = 0.80, and Hardy-Weinberg equilibrium p-value > or = 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. RESULTS:The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 x 10(-6)) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 x 10(-8)) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1). CONCLUSION:Our results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes. These hypothesis generating data illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging, and could be used to replicate observations made in other studies.

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Whole genome sequence analyses of brain imaging measures in the Framingham Study.

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