Dataset Information

Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain.

ABSTRACT: OBJECTIVES:The thickness of the brain's cortical gray matter (GM) and the fractional anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory with age. The two measures are positively correlated and may be modulated by common biological mechanisms. We employed four types of genetic analyses to localize individual genes acting pleiotropically upon these phenotypes. METHODS:Whole-brain and regional GM thickness and FA values were measured from high-resolution anatomical and diffusion tensor MR images collected from 712, Mexican American participants (438 females, age?=?47.9?±?13.2?years) recruited from 73 (9.7?±?9.3 individuals/family) large families. The significance of the correlation between two traits was estimated using a bivariate genetic correlation analysis. Localization of chromosomal regions that jointly influenced both traits was performed using whole-genome quantitative trait loci (QTL) analysis. Gene localization was performed using SNP genotyping on Illumina 1M chip and correlation with leukocyte-based gene-expression analyses. The gene-expressions were measured using the Illumina BeadChip. These data were available for 371 subjects. RESULTS:Significant genetic correlation was observed among GM thickness and FA values. Significant logarithm of odds (LOD???3.0) QTLs were localized within chromosome 15q22-23. More detailed localization reported no significant association (p?

SUBMITTER: Kochunov P

PROVIDER: S-EPMC3199541 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain.

Kochunov Peter P Glahn David C DC Nichols Thomas E TE Winkler Anderson M AM Hong Elliot L EL Holcomb Henry H HH Stein Jason L JL Thompson Paul M PM Curran Joanne E JE Carless Melanie A MA Olvera Rene L RL Johnson Matthew P MP Cole Shelley A SA Kochunov Valeria V Kent Jack J Blangero John J

Frontiers in neuroscience 20111019

<h4>Objectives</h4>The thickness of the brain's cortical gray matter (GM) and the fractional anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory with age. The two measures are positively correlated and may be modulated by common biological mechanisms. We employed four types of genetic analyses to localize individual genes acting pleiotropically upon these phenotypes.<h4>Methods</h4>Whole-brain and regional GM thickness and FA values were measured from hig ...[more]

PMID: 22028680

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Project description:Diffusion tensor cardiac magnetic resonance (DT-CMR) enables probing of the microarchitecture of the myocardium, but the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) reported in healthy volunteers have been inconsistent. The aim of this study was to validate a stimulated-echo diffusion sequence using phantoms, and to assess the intercentre reproducibility of in-vivo diffusion measures using the sequence.A stimulated-echo, cardiac-gated DT-CMR sequence with a reduced-field-of-view, single-shot EPI readout was used at two centres with 3 T MRI scanners. Four alkane phantoms with known diffusivities were scanned at a single centre using a stimulated echo sequence and a spin-echo Stejskal-Tanner diffusion sequence. The median (maximum, minimum) difference between the DT-CMR sequence and Stejskal-Tanner sequence was 0.01 (0.04, 0.0006) × 10(-3) mm2/s (2%), and between the DT-CMR sequence and literature diffusivities was 0.02 (0.05, 0.006) × 10(-3) mm2/s (4%).The same ten healthy volunteers were scanned using the DT-CMR sequence at the two centres less than seven days apart. Average ADC and FA were calculated in a single mid-ventricular, short axis slice. Intercentre differences were tested for statistical significance at the p?<?0.05 level using paired t-tests. The mean ADC?±?standard deviation for all subjects averaged over both centres was 1.10?±?0.06 × 10(-3) mm2/s in systole and 1.20?±?0.09 × 10-3 mm2/s in diastole; FA was 0.41?±?0.04 in systole and 0.54?±?0.03 in diastole. With similarly-drawn regions-of-interest, systolic ADC (difference 0.05 × 10(-3) mm2/s), systolic FA (difference 0.003) and diastolic FA (difference 0.01) were not statistically significantly different between centres (p?>?0.05), and only the diastolic ADC showed a statistically significant, but numerically small, difference of 0.07 × 10(-3) mm2/s (p?=?0.047). The intercentre, intrasubject coefficients of variance were: systolic ADC 7%, FA 6%; diastolic ADC 7%, FA 3%.This is the first study to demonstrate the accuracy of a stimulated-echo DT-CMR sequence in phantoms, and demonstrates the feasibility of obtaining reproducible ADC and FA in healthy volunteers at separate centres with well-matched sequences and processing.

Project description:ImportanceSchizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive.ObjectiveTo investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci.Design, setting, and participantsIndependent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021.Main outcomes and measuresThe primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci.ResultsBased on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified.Conclusions and relevanceThis study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

Dataset Information

Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain.

Publications

Genetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain.

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