Genetic influences vary by age and sex: Trajectories of the association of cholinergic system variants and theta band event related oscillations.
- Authors
- Chorlian, David B; Meyers, Jacquelyn L; Manz, Niklas; Zhang, Jian; Kamarajan, Chella; Pandey, Ashwini; Wang, Jen-Chyong; Plawecki, Martin; Edenberg, Howard; Goate, Alison; Tischfield, Jay; Porjesz, Bernice
- Year
- 2023
- Journal
- bioRxiv : the preprint server for biology
- PMID
- 36909650
- DOI
- 10.1101/2023.02.27.530318
- PMCID
- PMC10002625
To characterize systemic changes in genetic effects on brain development, the age variation of the associations of cholinergic genetic variants and theta band event-related oscillations (EROs) was studied in a sample of 2140 adolescents and young adults, ages 12 to 25 from the COGA prospective study. The theta band EROs were elicited in visual and auditory oddball (target detection) tasks and measured by EEG recording. Associations were found to vary with age, sex, task modality (auditory or visual), and scalp locality. Seven of the twenty-one muscarinic and nicotinic cholinergic SNPs studied in the analysis, from , , , and , had significant effects on theta band EROs with considerable age spans for some sex-modality combination. No SNP-age-modality combination had significant effects in the same direction for males and females. Results suggest that nicotinic receptor associations are stronger before age 18, while muscarinic receptor associations are stronger after age 18.
Theta ERO trajectories.Theta ERO total power trajectory means in auditory (left column) and visual (right column) modalities presented in two views: Top row: Development curves; Bottom row: Rates of change of development curves: Each line in this graph represents the slope of the corresponding line in the graph in the top row at the corresponding age. The y-axis is inverted in order to more clearly illustrate the decrease in absolute value of the slopes with time. Line styles and colors of the bottom graph follow the legend in the top row.
Examples of Association Trajectories:Rows 1 and 3: Genotypic effects of Cholinergic SNPs on Frontal Auditory ERO trajectories from regression model. Solid: Males, Dashed: Females; Blue: 0 Major Alleles, Green: 1 Major Allele, Red: 2 Major Alleles. Rows 2 and 4: Genotypic association effect size (of major allele) trajectories: Blue: Male; Red: Female. Thicker lines indicate significant effect sizes, which correspond to greater inter-allelic distances in Rows 1 and 3
Identification of significant SNPs.Significant SNP-phenotype associations in the auditory modality. Color coding indicates signed value of significant median effect sizes over 3 year age ranges and all scalp locations.
Significant sex differences in association.Significant SNP-phenotype male-female differences in associations in the auditory and visual modalities. Color coding indicates signed value of significantly different (male - female) median effect sizes over 3 year age ranges and all scalp locations.
Identification of significant SNPs from the covariance structure of the genotype-phenotype associations.SNPs associated with phenotypic variance determined by the first component from age-specific sparse PCA. The sparsity constraint limits number of SNPs to parallel control by FDR threshold.
Discrimination of phenotypes by genotypic profile.Age specific phenotype-sex pairs for four age ranges in the space defined by the first two principal components of SNP profiles from age-specific sparse PCA. The positions of the phenotypes are particular to the individual plots, since the axes differ for each plot.
Median p-value.
Permutation test results.
Sparse PCA comparison with bootstrap frequency of occurance.
| # | Section | Preview |
|---|---|---|
| 20 | Data collection and analysis — Genotyping: | Genotyping was performed at Washington University School of Medicine in St. Louis on an OpenArray… |
| 21 | Data collection and analysis — Electrophysiology: | One important indicator of neurocognitive function is the P3 (or P300) response, evidenced in by the… |
| 22 | Retrospective view | The above sections represent the work of the authors as of early 2017. Since that time our thinking… |
| 23 | Retrospective view | Methods for structural analysis involve aggregation over phenotypes and over genotypes to create new… |
| 24 | Retrospective view — Statistical Supplement: | The following material is derived from documents which were antecedents of the presentation text;… |
| 25 | Statistical Methodology for the Analysis of Association Trajectories — Introduction | This study integrates the methods from both gene association studies and gene expression studies to… |
| 26 | Statistical Methodology for the Analysis of Association Trajectories — Introduction | this study the complexity of the association relations necessitated the use of age specific PCAs, as… |
| 27 | Statistical Methodology for the Analysis of Association Trajectories — Analysis of Association Trajectories | Extending a previous study of the development of theta band EROs (Chorlian et al., 2015) and as used… |
| 28 | Statistical Methodology for the Analysis of Association Trajectories — Analysis of Association Trajectories | In this study, the primary object of the analyses are the effect sizes of the SNPs obtained from the… |
| 29 | Statistical Methodology for the Analysis of Association Trajectories — Analysis of Association Trajectories | As there are 5912 observations spread over a 13 year age-range, there is sufficient data to provide… |
| 30 | Statistical Methodology for the Analysis of Association Trajectories — Analysis of Association Trajectories | a non-parametric bootstrap method with 1000 resamplings. The bootstrapping process is described in… |
| 31 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs | To characterize the age specific variation of genotypic effects on the phenotypic variables,… |
| 32 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by thresholding p-values by false discovery rate | The evaluation of the significance of the association of the individual SNPs with theta EROs is… |
| 33 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by thresholding p-values by false discovery rate | Specifically, the distribution of p-values from non-associated SNP-phenotype pairs should be uniform… |
| 34 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by thresholding p-values by false discovery rate | In the interest of condensation of information and ease of interpretation, as well as the… |
| 35 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by concentration of effect sizes | To determine whether large effect sizes were distributed randomly across SNPs for sets of correlated… |
| 36 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by concentration of effect sizes | As was done for the p-values, to simplify the analysis of age variation in the association… |
| 37 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by concentration of effect sizes | In order to identify the significant SNPs, the values of the age-range averaged absolute effect… |
| 38 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by concentration of effect sizes | Permutation tests were carried out to test the null hypothesis that the distribution of the averaged… |
| 39 | Statistical Methodology for the Analysis of Association Trajectories — Identification of significant SNPs — Significant SNPs identified by concentration of effect sizes | pseudo-SNPs. That is, 9 distinct permutations of the effect sizes of the 21 SNPs are produced, one… |
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Non-linear development of EEG coherence in adolescents and young adults shown by the analysis of neurophysiological trajectories and their covariance | Chorlian DB et al. | — | 2024 | — |