Imaging Genetic Analysis for PNC Behavioral Data. Department of Statistics and Operations Research Liuqing (Jasmine) Yang May 6 th, 2016

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1 Imaging Genetic Analysis for PNC Behavioral Data Department of Statistics and Operations Research Liuqing (Jasmine) Yang May th, 1

2 PNC: Philadelphia Neurodevelopmental Cohort A research initiative focusing on characterizing brain and behavior interaction in youths A sex, age stratified sample of 87 individuals from the greater Philadelphia area, ages 81 years old v Behavioral data (clinical and cognitive phenotypes) v Neuroimaging data (MRI, fmri, DTI, ASL perfusion) v Genetic information (SNPs)

3 PNC: Philadelphia Neurodevelopmental Cohort Behavioral Data sample size: 8+ sample size: <1 Imaging Data Genomic Data sample size: 8+

4 Computerized Neurocognitive Battery (CNB) A 1-hr cognitive neuroscience-based computerized battery, 1 tests measuring accuracy and speed for neurobehavioral domains (Gur et al. 1) o Executive-Control/ Episodic Memory/ Complex Cognition/ Social Cognition/ Sensorimotor o 8 test summary scores (shifted-log transformation to achieve approximate normality. Feng et al. 1)

5 Validity of the battery AGE PCET PCPT LNB PWMT PFMT VOLT PVRT PMAT PLOT PEIT PEDT PADT Accuracy AGE PCET PCPT LNB PWMT PFMT VOLT PVRT PMAT PLOT PEIT PEDT PADT MP TAP Speed Measures more highly intercorrelated for speed (lower triangle) than for accuracy (upper triangle) Greater intercorrelations within memory measures, but most ranges from moderate to nil Support the construct validity of CNB (Gur et.al 1)

6 GWAS study on 8 cognitive summary scores Regression model: Individual test scores = Gender + Age + SNP PC scores + SNP i SNPs: Additive model, ~ millions Simple but worked (QQ plots and Manhattan plots to be shown)

7 GWAS results: selected QQ plots

8 GWAS results: selected Manhattan plots

GWAS results for Working Memory Test (LNB) LNB- Accuracy Chr 8 locus 1: associate with gene CSMD1 (CUB and Sushi multiple domains 1) - CSMD1 has reached genome- wide support as a risk factor for

9 GWAS results for Working Memory Test (LNB) LNB- Accuracy Chr 8 locus 1: associate with gene CSMD1 (CUB and Sushi multiple domains 1) - CSMD1 has reached genome- wide support as a risk factor for schizophrenia. There is initial but inconclusive evidence for a role of this variant in aspects of cognition. (Bitsios et al. 1) Chr 8 locus : associate with gene STMN (stathmin ) - STMN is neural enriched, thought to be nervous system- specific. (Curmi et al. 3)

10 Any shared significant SNPs among 8 measures? Highest frequency: 3/8 SNP Gene Chr BP PCET- AC VOLT- SP WRAT- RAW rs183 CSMD E- 1.3E- 3.E- Most significant SNPs (p-value < 1 - ) are not overlapping with each other Alternative ways to detect signals? v Gene level (allow paralogs) v Functional level v Pathway level?

11 Summarizing GWAS results: alternative levels Gene Symbol # of Occurrence (out of 8) Related Function/Disorder * CSMD1; CSMD 18 Schizophrenia CDH; CDH9; CDH13; CDH18; CDH19; CDH; CDH3 17 CNTN1; CNTN; CNTN; CNTN; ROBO1; ROBO 1 Integral membrane proteins that mediate calcium- dependent cell- cell adhesion, overexpressed in brain, etc. Neuronal membrane protein, functions as a cell adhesion molecule/functions in axon guidance and neuronal precursor cell migration AGBL1; AGBL3; AGBL 1 Corneal disease Gene Family Name Genes # of Occurrence Related Function/Disorder* Voltage- gated K + KCNB1, KCND3, KCNG, Highly expressed in brain, channels KCNH1, KCNJ, KNCQ 17 neurotransmitter system * Annotation from GeneCards.org

Summarizing GWAS results: alternative levels Gene Family Name Genes Voltage- gated K+ channels KCNB1, KCND3, KCNG, KCNH1, KCNJ, KNCQ # of Occurrence 17 Gene Symbol DLG Related Function/Disorder*

12 Summarizing GWAS results: alternative levels Gene Family Name Genes Voltage- gated K+ channels KCNB1, KCND3, KCNG, KCNH1, KCNJ, KNCQ # of Occurrence 17 Gene Symbol DLG Related Function/Disorder* Highly expressed in brain, neurotransmitter system # of Occurrence Related Function* 7 may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. * Annotation from GeneCards.org

13 Brain is a network! Independence can t exist in a complex system, which may be limiting our understanding of the brain (Dr. Paul Laurienti, Wake Forest University) Alternative tools to detect the association between two data types? [Behavioral + Genomic] ü Joint and Individual Variation Explained (JIVE): variation decomposition for integrated analysis

14 JIVE: variation decomposition *Figure credit: Qing Feng

15 JIVE set-up & results DataX: 8 behavioral variables no missing value DataY: 111 SNPs (p-value < 1 - ) identified from previous GWAS study Sample size: n = 19 Ø Results: Identified one joint component - direction on which DataX and DataY create the same subject contrast

16 Loadings of Cognitive Test on the joint component Accuracy measure works more similarly with genetics than Speed measure does Shown to have substantial heritability (Gur et al 1) WRAT measuring IQ PVRT measuring verbal reasoning ability PCET measuring abstraction and concept formation LNB measuring working memory

17 PNC Datasets Behavioral Data sample size: 8+ sample size: <1 Imaging Data Genomic Data sample size: 8+

18 MRI: FreeSurfer volumetric output of 3 ROIs Area Thickness Volume *Figure credit: Desikan et al,

19 PNC Datasets Smaller sample size (<1 subjects) Variation explained by age/gender/ethnicity Remove by multivariate regression Imaging Data Behavioral Data Genomic Data

20 Projection on to PCs colored by AGE PC PC PC After - PC Age PC PC -1 PC PC. Age Before PC.1 PC.1 Age MRI Thickness.1 PC. Behavioral.1 Age PC Matlab plotting codes: Dr. Steve Marron.

21 1. African 1. Other.3 Asian. American.1 Hawaiian PC.3.. African Other -1 Asian.1 1 Caucasian PC PC American. -1 Hawaiian PC After. PC PC PC PC PC PC Hawaiian African American MRI Thickness Caucasian Before Other -1 Asian Hawaiian American Asian PC 1 Other African Caucasian Caucasian. MRI Area Projection on to PCs colored by Ethnicity. 1 1 PC.

22 JIVE set-up & results [BH + area:thickness] DataX: 8 behavioral variables no missing value DataY: area + thickness measure for 8 ROIs (Remark: Correlation between volume and thickness area was very high) Sample size: n = 3 Ø Results: joint component identified

23 1 1 JIVE [BH + area:thickness] 1 st Component. Loadings of Variables for Joint Behavioral. Loadings of Variables for Individual Behavioral Loadings Loadings WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Loadings Loadings of Variables for Separate Behavioral WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Top 1 ROIs Absolute loading lh_precuneus_area.1 lh_superiorfrontal_area.139 rh_fusiform_area.13 rh_superiorfrontal_area.13 rh_rostralmiddlefrontal_area.13 lh_lateralorbitofrontal_area.13 rh_superiortemporal_area.131 lh_rostralanteriorcingulate_area.19 lh_fusiform_area.17 lh_insula_area.1

24 1 1 JIVE [BH + area:thickness] nd Component. Loadings of Variables for Joint Behavioral.. Loadings of Variables for Individual Behavioral Loadings Loadings WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Loadings WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC Loadings of Variables for Separate Behavioral VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Top 1 ROIs Absolute loading rh_precentral_thickness.1 lh_superiorparietal_thickness.1 lh_caudalmiddlefrontal_thickness.1 lh_precentral_thickness.13 rh_precuneus_thickness.19 lh_paracentral_thickness.18 rh_superiorparietal_thickness.18 lh_superiorfrontal_thickness.1 lh_lingual_thickness.1 lh_precuneus_thickness.1

25 JIVE Results Interpretation Accuracy associates more with area in making similar individual contrast, while speed vs. thickness Better resolution? BH + area vs. BH + thickness

26 JIVE [BH + Area] 1 st Component. Loadings of Variables for Joint Behavioral. Loadings of Variables for Individual Behavioral Executive Control Complex Cognition..1 Loadings WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Loadings WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Loadings Loadings of Variables for Separate Behavioral WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Top 1 ROIs Absolute loading lh_precuneus_area.13 rh_superiorfrontal_area.1 rh_rostralmiddlefrontal_area.1 lh_superiorfrontal_area.1 rh_fusiform_area.1 rh_superiortemporal_area.17 lh_fusiform_area.17 rh_middletemporal_area.1 lh_rostralmiddlefrontal_area.1 lh_lateralorbitofrontal_area.1

27 JIVE [BH + Thickness] 1 st Component. Loadings of Variables for Joint Behavioral. Loadings of Variables for Individual Behavioral Loadings Loadings WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Loadings Loadings of Variables for Separate Behavioral WRAT-RAW WRAT-STD PCET-AC PCPT-AC LNB-AC PWMT-AC PFMT-AC VOLT-AC PVRT-AC PMAT-AC PLOT-AC PEIT-AC PEDT-AC PADT-AC PCET-SP PCPT-SP LNB-SP PWMT-SP PFMT-SP VOLT-SP PVRT-SP PMAT-SP PLOT-SP PEIT-SP PEDT-SP PADT-SP MP-SP TAP-SP Top 1 ROIs Absolute loading lh_superiorfrontal_thickness.177 lh_lingual_thickness.173 lh_superiorparietal_thickness.171 lh_caudalmiddlefrontal_thickness.171 lh_precuneus_thickness.17 rh_superiorfrontal_thickness.1 rh_lingual_thickness.13 rh_superiorparietal_thickness.11 rh_caudalmiddlefrontal_thickness.1 lh_cuneus_thickness.19

Conclusion/Future steps Behavioral Data Association between anatomic structure and cognitive performance Imaging Data Genomic Data Identified overlapped

28 Conclusion/Future steps Behavioral Data Association between anatomic structure and cognitive performance Imaging Data Genomic Data Identified overlapped significant genes GWAS on ICV, WM, or resfmri by colleagues Future Steps: Ø Integrate information from all three datasets Ø Incorporate clinic assessment results

29 Thank you!

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.

Supplementary Figure 1: Attenuation of association signals after conditioning for the lead SNP. a) attenuation of association signal at the 9p22.32 PCOS locus after conditioning for the lead SNP rs10993397;