A Cross-Diagnostic GWAS of Longitudinal Executive Function ... · A Cross-Diagnostic GWAS of...
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A Cross-Diagnostic GWAS of Longitudinal Executive Function Profile Scores Urs Heilbronner 1 , Bernadee Wendel 2 , Monika Budde 1 , Katrin Gade 1 , Krisna Adorjan 1 , Janos L. Kalman 1 , Fanny Senner 1 , Till F. M. Andlauer 3 , Ashley L. Comes 1 , Eva C. Schulte 1 , Sergi Papiol 1 , Heike Bickeböller 2 and Thomas G. Schulze 1 1 Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany 2 Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany 3 Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany Introduction Execuve funcons (EFs) concern the cognion involving con- trol and coordinaon of mental processes. They are impaired in severe mental disorder such as bipolar disorder and schizo- phrenia. Here, we study the genec underpinnings of paent course over me in two core aspects of EFs: set-shiſting and up- dang. We use data of the longitudinal PsyCourse study (Bud- de et al., 2018). In this mul-center study, paents from the af - fecve-to-psychoc connuum (n=1047) were assessed at four measurement points across a period of 1.5 years. Methods Phenotypes The Trail-Making-Test, Part B (TMT-B) and the Verbal Digit Span Back - wards (VDS) were used to assess set-shiſting and updang compo- nents of EFs, respecvely. All paents with at least three measure- ment points over me were analyzed, resulng in n=356 (TMT-B) and n=364 (VDS) individuals. We used a summary measurement, the area under the curve with respect to the increase (AUC I ), to compute cognive profiles scores that provide a measure of an indi- vidual’s longitudinal change over me. To impute missing scores at certain me points, we employed the R package Hmisc, using mul- ple imputaon, and creang mulple data sets (TMT-B: 10; VDS: 7). In each single data-set we calculated the AUC I for all individuals, thus yielding mulple phenotypes. Genotyping, imputaon and analysis of genec variants Paents were genotyped with the Illumina PsychArray and common variants (MAF≥0.01) were imputed using the 1000 Genomes Phase 3 reference panel. We performed a GWAS for mulple phenotypes with PLINK 1.9, using linear regression with seven different covari- ates (age, sex, clinical center and four principal components from ancestry muldimensional scaling). We applied Rubin’s Rule to pool the mulple GWAS outputs. Discussion Despite finding no GWAS-significant hits, our results suggest longi- tudinal changes in EFs to be putavely associated with intracellu- lar funcon (TMT-B) and pathways affected by neurodegenerave disease (VDS). We will further research these phenotypes when more paents of the PsyCourse study are genotyped. Grants TGS: DFG Grants SCHU 1603/5-1 and SCHU 1603/7-1; BMBF Grants IntegraMent and BipoLife; Dr. Lisa-Oehler-Foundaon (Kassel, Ger - many). HB: DFG Grants BI 576/5-1 and Research Training Group “Scaling Problems in Stascs” RTG 1644. Results We did not observe GWAS-significant hits. For the TMT-B, the top three variants were rs187822633 (chromosome (Chr) 2, p=5.95x10 -7 , β=738.1, 95% confidence interval (95% CI)=(722.9, 753.2)), rs79496814 (Chr 12, p=1.86x10 -6 , β=-236.6, 95% CI=(-241.7, -231.5)), and rs139931071 (Chr 10, p=2.75 x10 -6 , β=-1211.7, 95% CI=(-1238.2, -1185.2)). Rs187822633 is an intron variant in the “Leucine Rich Pen- tatricopepde Repeat Containing” gene that is involved in cytoskele- tal organizaon, vesicular transport, and transcriponal regulaon. Rs79496814 and rs139931071 are both intron variants in the genes for “Transmembrane and Tetratricopepde Repeat Containing 2” and “Signal Transducing Adaptor Molecule”, respecvely, and both proteins have funconal roles as cellular adaptor molecules. The top three variants for VDS were rs200013838 (Chr 7, p=3.73x10 -7 , β=-42.3, 95% CI=(-43.2, -42.5)), rs61433316 (Chr 2, p=8.48x10 -7 , β=- 24.7, 95% CI=(-25.2, -24.2)), and rs56280536 (Chr 2, p=8.48x10 -7 , β=-24.7, 95% CI=(-25.3, -24.2)). Rs200013838 is an intron variant in the “Family with Sequence Similarity 3 Member C” gene, which en- codes a secreted protein that has been associated with Alzheimer’s Disease (e.g. Hasegawa et al., 2014). Rs61433316 and rs56280536 are located near the gene for long intergenic non-protein coding RNA 1866. References Budde et al. (2018), Am J Med Genet B Neuropsychiatr Genet doi: 10.1002/ajmg.b.32639. Eekhout et al. (2017), BMC Med Res Methodol 17:129. Hasegawa et al. (2014), Nat Commun 5:3917. Pruessner et al. (2003), Psychoneuroendocrinology 28:916-931. Figure 1. Longitudinal profile scores (AUC I s; Pruessner et al., 2003, leſt) are created by impung missing phenotype values using mul- ple imputaon (Eekhout et al., 2017, middle). The AUC I s of each individual imputaon are used as phenotypes in GWA studies (right). Results of each imputaon are pooled aſterwards to obtain a single p-value for each genec variant. Figure 2. QQ- and Manhaan plots of both GWAS.
Transcript of A Cross-Diagnostic GWAS of Longitudinal Executive Function ... · A Cross-Diagnostic GWAS of...
A Cross-Diagnostic GWAS of Longitudinal Executive Function Profile Scores
Urs Heilbronner1, Bernadette Wendel2, Monika Budde1, Katrin Gade1, Kristina Adorjan1, Janos L. Kalman1, Fanny Senner1, Till F. M. Andlauer3, Ashley L. Comes1, Eva C. Schulte1, Sergi Papiol1, Heike Bickeböller2 and Thomas G. Schulze1
1Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Germany 2Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany 3Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
IntroductionExecutive functions (EFs) concern the cognition involving con-trol and coordination of mental processes. They are impaired in severe mental disorder such as bipolar disorder and schizo-phrenia. Here, we study the genetic underpinnings of patient course over time in two core aspects of EFs: set-shifting and up-dating. We use data of the longitudinal PsyCourse study (Bud-de et al., 2018). In this multi-center study, patients from the af-fective-to-psychotic continuum (n=1047) were assessed at four measurement points across a period of 1.5 years.
MethodsPhenotypesThe Trail-Making-Test, Part B (TMT-B) and the Verbal Digit Span Back-wards (VDS) were used to assess set-shifting and updating compo-nents of EFs, respectively. All patients with at least three measure-ment points over time were analyzed, resulting in n=356 (TMT-B) and n=364 (VDS) individuals. We used a summary measurement, the area under the curve with respect to the increase (AUCI), to compute cognitive profiles scores that provide a measure of an indi-vidual’s longitudinal change over time. To impute missing scores at certain time points, we employed the R package Hmisc, using mul-tiple imputation, and creating multiple data sets (TMT-B: 10; VDS: 7). In each single data-set we calculated the AUCI for all individuals, thus yielding multiple phenotypes.
Genotyping, imputation and analysis of genetic variants Patients were genotyped with the Illumina PsychArray and common variants (MAF≥0.01) were imputed using the 1000 Genomes Phase 3 reference panel. We performed a GWAS for multiple phenotypes with PLINK 1.9, using linear regression with seven different covari-ates (age, sex, clinical center and four principal components from ancestry multidimensional scaling). We applied Rubin’s Rule to pool the multiple GWAS outputs.
DiscussionDespite finding no GWAS-significant hits, our results suggest longi-tudinal changes in EFs to be putatively associated with intracellu-lar function (TMT-B) and pathways affected by neurodegenerative disease (VDS). We will further research these phenotypes when more patients of the PsyCourse study are genotyped.
GrantsTGS: DFG Grants SCHU 1603/5-1 and SCHU 1603/7-1; BMBF Grants IntegraMent and BipoLife; Dr. Lisa-Oehler-Foundation (Kassel, Ger-many).HB: DFG Grants BI 576/5-1 and Research Training Group “Scaling Problems in Statistics” RTG 1644.
ResultsWe did not observe GWAS-significant hits. For the TMT-B, the top three variants were rs187822633 (chromosome (Chr) 2, p=5.95x10-7, β=738.1, 95% confidence interval (95% CI)=(722.9, 753.2)), rs79496814 (Chr 12, p=1.86x10-6, β=-236.6, 95% CI=(-241.7, -231.5)), and rs139931071 (Chr 10, p=2.75 x10-6, β=-1211.7, 95% CI=(-1238.2, -1185.2)). Rs187822633 is an intron variant in the “Leucine Rich Pen-tatricopeptide Repeat Containing” gene that is involved in cytoskele-tal organization, vesicular transport, and transcriptional regulation. Rs79496814 and rs139931071 are both intron variants in the genes for “Transmembrane and Tetratricopeptide Repeat Containing 2” and “Signal Transducing Adaptor Molecule”, respectively, and both proteins have functional roles as cellular adaptor molecules. The top three variants for VDS were rs200013838 (Chr 7, p=3.73x10-7, β=-42.3, 95% CI=(-43.2, -42.5)), rs61433316 (Chr 2, p=8.48x10-7, β=-24.7, 95% CI=(-25.2, -24.2)), and rs56280536 (Chr 2, p=8.48x10-7, β=-24.7, 95% CI=(-25.3, -24.2)). Rs200013838 is an intron variant in the “Family with Sequence Similarity 3 Member C” gene, which en-codes a secreted protein that has been associated with Alzheimer’s Disease (e.g. Hasegawa et al., 2014). Rs61433316 and rs56280536 are located near the gene for long intergenic non-protein coding RNA 1866.
ReferencesBudde et al. (2018), Am J Med Genet B Neuropsychiatr Genet doi: 10.1002/ajmg.b.32639. Eekhout et al. (2017), BMC Med Res Methodol 17:129.Hasegawa et al. (2014), Nat Commun 5:3917.Pruessner et al. (2003), Psychoneuroendocrinology 28:916-931.
Figure 1. Longitudinal profile scores (AUCIs; Pruessner et al., 2003, left) are created by imputing missing phenotype values using multi-ple imputation (Eekhout et al., 2017, middle). The AUCIs of each individual imputation are used as phenotypes in GWA studies (right). Results of each imputation are pooled afterwards to obtain a single p-value for each genetic variant.
Figure 2. QQ- and Manhattan plots of both GWAS.
