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Report for Clinical Trial NCT00570583

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Clinical Studies of Mental Illness Not Involving Treatment Development, Efficacy, or Effectiveness Trials Phenotype-genotype Predictors of Cognitive Outcomes in Geriatric Depression

Late-life depression (LLD) and cognitive impairment (CI) are significant public health problems among older adults, and their co-occurrence markedly increases disease burden and dementia risk. This highlights the importance of identifying and treating CI in LDD; however, current lack of reliable prognostic information from clinical, neuroimaging, and genetic data impedes research on targeted prevention and treatment. Two critical ways to close current knowledge gaps in predicting cognitive diagnostic outcomes of LLD involve: 1) increasing the number of diagnostic cases available to existing studies, and 2) using those studies to identify clinical, imaging, and genetic predictors that will improve future diagnosis. We intend to do both in the current proposal. We plan to study the following SPECIFIC AIMS: Aim 1: Identify baseline clinical-behavioral predictors of cognitive diagnostic outcomes in LLD. Working hypothesis: During acute LLD, CN will be associated with more frequent EOD and higher negative life stress than PCI and AD; PCI will be associated with EOD and higher frailty than CN and AD; AD will be associated with LOD, greater appetite loss, lower anxiety, and greater memory impairment than CN and PCI. Aim 2: Use multimodal neuroimaging at baseline to identify patterns associated with cognitive diagnostic outcomes in individuals with LLD. Working Hypothesis: CN will be associated with greater white matter integrity compared with PCI and AD; PCI will be associated with lower white matter integrity and network abnormalities in anterior cingulate cortex compared with CN; AD will be associated with lower hippocampal volume compared with CN and PCI. Aim 3: (exploratory): Explore interrelationships among candidate genes, cognitive diagnostic outcomes, and proposed phenotypic components relevant to LLD. Exploratory Hypotheses: 1) COMT val158met polymorphism will be associated with CN; 2) 5-HTTPRL and APOE ε2 polymorphisms will be associated with frailty; 3) genetic variation (SNPs) in TPH2 and AGTR1 will be associated with risk factors of AD: LOD, episodic memory, hippocampal volume, and appetite loss.

NCT00570583 Major Depression Dementia
MeSH:Dementia Depression Depressive Disorder
HPO:Dementia Depressivity


Primary Outcomes

Measure: Change in Depression status (measured by Montgomery Asberg Depression Rating Scale)

Time: Minimum of once per year, up to 21 years

Measure: Change in Cognitive impairment (as measuring using cognitive tests including those found in the CERAD battery)

Time: Once per year, up to 21 years

Measure: Development of dementia (Determined by Clinical Consensus Conference)

Time: once per year, up to 14 years

Secondary Outcomes

Measure: Change in Cognition (as measured by tests including those in the CERAD battery) Change in Brain MRI markers (e.g., volume of white matter and gray matter lesions)

Time: once per year, up to 21 years

Measure: Change in Impairment in Instrumental or Basic Activities of Daily Living

Time: at least once per year, up to 21 years

Measure: Packing density of prefrontal cortex neurons with pyramidal morphology in post-mortem neuroanatomical studies

Time: once post-mortem

Time Perspective: Prospective

Case-Control


There is one SNP

SNPs


1 V158M

Exploratory Hypotheses: 1) COMT val158met polymorphism will be associated with CN; 2) 5-HTTPRL and APOE ε2 polymorphisms will be associated with frailty; 3) genetic variation (SNPs) in TPH2 and AGTR1 will be associated with risk factors of AD: LOD, episodic memory, hippocampal volume, and appetite loss. --- val158met ---

Specifically, CN individuals will have earlier first onset of depression (EOD) relative to AD, more negative life stress during acute depression compared with AD and PCI, and greater white matter integrity; CN will also be associated with the AA genotype of the COMT val158met polymorphism, which may confer both neuroprotection and higher stress sensitivity. --- val158met ---



HPO Nodes


HPO:
HP:0000726: Dementia
Genes 277
FUS PSEN2 MBTPS2 PLA2G6 HEXA C9ORF72 HTT ND5 ATXN10 SNCAIP MAPT TRNS2 TWNK GBA POLG JPH3 NOTCH3 APOE TMEM106B GM2A PSEN1 APP COL4A1 MECP2 PRKN DNMT1 POLG PRDX1 CISD2 GRN TREM2 COX3 GRN SNCA APOE ADH1C CHMP2B FMR1 TRNS1 PRNP APP TUBA4A UCHL1 VPS13C GLUD2 ATXN2 TBK1 TRNF MAPT CSTB WFS1 ATP6 PPP2R2B PRNP XPR1 MAPT MAPT FTL NOS3 VCP DNM1L TYROBP SNCA C9ORF72 CSF1R PRNP TRNW SDHA CYTB WFS1 SNCB ZFYVE26 ARSA JPH3 PSEN2 CHMP2B APP SNCA TREM2 DGUOK EPM2A C9ORF72 ATXN2 APP PODXL MAPT LRRK2 ERCC8 HTRA2 DCTN1 TMEM106B HTRA1 GBA2 C19ORF12 HNRNPA2B1 SERPINI1 PLA2G6 CP CFAP43 PRNP CP APP HLA-DQB1 AARS2 VCP SNCA ND1 WDR45 MATR3 HTRA1 VPS35 MAPT MATR3 HTT C9ORF72 ATXN3 SNCA PANK2 TUBB4A GBA2 CHMP2B PRICKLE1 NR4A2 ATN1 ADA2 WDR45 LRRK2 PARK7 NHLRC1 TTR SQSTM1 ASAH1 VCP ERCC4 GIGYF2 APP ATP13A2 COX2 UBQLN2 HNRNPA1 DNAJC13 TRNK ATN1 VPS13A AMN CHMP2B HTT TOMM40 TYROBP SLC2A3 PRNP CLN3 SQSTM1 CST3 SDHAF1 PRNP ROGDI FBXO7 APP SDHB TRNV NPC2 ATP13A2 ABCD1 CHCHD10 SPG21 ATP6V1A GBA CERS1 PSEN1 PNPLA6 SPG21 APTX TREM2 TRNL1 RNF216 CLN6 ITM2B VPS13C GBA C9ORF72 GBA TBK1 PDGFB GBE1 MAPT DNAJC5 MAPT TRNE ATXN2 GBA TREM2 EPM2A TREM2 MMACHC NPC1 PLAU TYMP TRPM7 PPP2R2B TREX1 MPO HFE SNCA OPA1 NDP SQSTM1 PINK1 PSEN1 CFAP43 LRRK2 CTSF FTL DNAJC6 TRNQ SPAST RNF216 PSAP FMR1 ALDH18A1 COX1 TMEM106B ITM2B IRF6 TIMM8A ASAH1 TBP TARDBP RRM2B ATXN8OS PSEN1 SLC13A5 PINK1 PRNP ATP6 PDGFRB SCARB2 EIF4G1 SORL1 HNRNPA2B1 CUBN ATP6V0A2 MAPT VCP ROGDI PSEN1 PANK2 ATP13A2 PSEN1 NOTCH2NLC KCTD7 PRDM8 ND6 PSEN1 GRN NOTCH3 ABCA7 VCP ALDH18A1 ATP7B VCP DNMT1 GRN NHLRC1 ATP13A2 CHCHD10 A2M PRKAR1B TBP CHMP2B ATP6V1E1 RAB39B CYP27A1 TRNC DCTN1 SDHD TARDBP
Protein Mutations 1
V158M
SNP 0
HP:0000716: Depressivity
Genes 381
TRNF ARSG FUS ANG PDE11A GLE1 SARS1 PLA2G6 NEK1 SLC18A2 HLA-DRB1 FMN2 TRNS2 XK SMPD1 HTT CHD7 ATXN10 SNCAIP TCF4 ATP1A3 GPR101 DRD2 PDGFB OPTN TWNK RRM2B GBA KCNT1 BCR JPH3 NOTCH3 PDCD1 PAH PIGC HTR2A PRKN DNMT1 TRNL1 ZC3H14 ST3GAL3 USH1G LMNB1 LIMK1 SNCA ADH1C ATRX OCRL PRKACA TBL2 FMR1 PRNP CPOX USP8 PPARGC1A UCHL1 VPS13C GLUD2 KCNJ2 TBK1 MST1 TWNK MSTO1 MAPT B3GALNT2 PPP2R2B PROKR2 PRNP XPR1 RPS20 POLG SQSTM1 ARMC5 NDST1 TRNN TARDBP USH2A TRNL2 GNAS DCPS STX16 TTC19 ATXN10 SLC20A2 TBX1 CSF1R GSN ND1 ATP7B CDH23 TAC3 MYO7A WFS1 TWNK PDGFRB HS6ST1 PRKCG ESPN COX2 HIRA GNAS CLCN4 CASR ARSA GABRA1 GCH1 DNA2 MAPT UBQLN2 GDAP2 FGF8 TOR1A SEMA4A TK2 UFD1 FUS DGUOK EPM2A HARS1 C9ORF72 POLG UNC13A PODXL TBK1 LRRK2 CLIP2 HTRA2 DCTN1 TRAPPC9 C19ORF12 PLA2G6 MATR3 C12ORF4 GRIK2 SLC6A4 PRNP MECP2 CP HLA-DQB1 CFAP410 CACNA1G MED23 AARS2 VCP TRNQ PRNP JMJD1C SRPX2 VAPB MYO7A SGCE CC2D1A VPS35 ABCA7 CCNF EHMT1 C9ORF72 SNCA MLH1 PANK2 DUSP6 CEP78 GABRB3 FIG4 NR4A2 BMPR1A PTPN22 PARK7 MECP2 DNMT1 WASHC4 TRNS1 CACNA1G AMACR VCP ALMS1 IDUA CHMP2B PMS1 GIGYF2 KISS1R TSC1 RPS6KA3 COQ2 ERBB4 KDM5B POLG2 SEC24C SLC2A1 COQ2 DNAJC13 MSTO1 MSH6 FBXO31 RRM2B CHMP2B HTT POLG EDC3 PGAP1 NSMF SLC25A4 ATXN2 PIK3CA THOC2 PER2 GLA CACNA1H TBC1D7 PAH SQSTM1 POLG GNAS PRNP AIMP1 ARMC5 CIB2 LINS1 GABRG2 FGFR1 C9ORF72 CDH23 METTL23 TACR3 EPCAM TRNS1 PPOX KRAS ANOS1 SLC45A1 WARS2 POLG FA2H COASY HLA-DQB1 GNAS TRNL1 PRSS12 CLN6 GBA PMS2 C9ORF72 CLCN4 HBB TSC2 PDGFB AIP PRKAR1A COMT MAPT DNAJC5 CRADD ATXN8 ATXN2 ATP13A2 ARVCF GTF2I WHRN GBA TRNW COX3 KISS1 TREM2 TGFBR2 PDZD7 AFG3L2 PDGFRB BCS1L MAN1B1 SNCA VCP NEFH TRNH COX1 ATP1A3 DAO CPOX PINK1 LRRK2 HMBS CRBN DCTN1 CTSF GPR35 CLIP1 TBX1 ND5 TAF15 ND4 PTS PON3 MED25 DNAJC6 TRNS2 NSUN2 FMO3 SPAST HMBS FGF17 ELN PON1 CBS CYP27A1 FGF14 PSAP FMR1 TMEM106B KCTD17 RREB1 CHCHD10 TWNK TBP AP2S1 ATXN8OS FRRS1L ATXN8OS BAZ1B HNMT FAN1 ADGRV1 PINK1 HNRNPA1 PRPH TUSC3 MBOAT7 PRNP PANK2 FGF14 GABRG2 KCTD17 PDGFRB TECR LMAN2L EIF4G1 GNAS CLRN1 EPHA4 GP1BB JRK IQSEC1 TREM2 MSH2 PSEN1 RFC2 PON2 MAPK1 SGCE PER3 PROK2 GRIN2A TNIK PFN1 MLH3 GRN ND6 CRKL ANXA11 C9ORF72 GNRHR EZR VCP USH1C GNRH1 TOR1A WFS1 POLG NHLRC1 CISD2 CHCHD10 WDR11 SPRY4 PPT1 PCDH15 TBP GTF2IRD1 SOD1 RSRC1 GLT8D1 DCTN1 GNA11 TARDBP