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1. Genomic influences on self-reported childhood maltreatment

Author

Dalvie, S, Maihofer, AX, Coleman, JR, Bradley, B, Breen, G, Brick, LA, Chen, C-Y, Choi, KW, Duncan, LE, Guffanti, G, Haas, M, Harnal, S, Liberzon, I, Nugent, NR, Provost, AC, Ressler, KJ, Torres, K, Amstadter, AB, Austin, SB, Baker, DG, Bolger, EA, Bryant, RA, Calabrese, JR, Delahanty, DL, Farrer, LA, Feeny, NC, Fiore, JD, Forbes, D, Galea, S, Gautam, A, Gelernter, J, Hammamieh, R, Jett, M, Junglen, AG, Kaufman, ML, Kessler, RC, Khan, A, Kranzler, HR, Lebois, LAM, Marmar, C, Mavissakalian, MR, McFarlane, A, O'Donnell, M, Orcutt, HK, Pietrzak, RH, Risbrough, VB, Roberts, AL, Rothbaum, AO, Roy-Byrne, P, Ruggiero, K, Seligowski, A, Sheerin, CM, Silove, D, Smoller, JW, Stein, MB, Teicher, MH, Ursano, RJ, Van Hooff, M, Winternitz, S, Wolff, JD, Yehuda, R, Zhao, H, Zoellner, LA, Stein, DJ, Koenen, KC, Nievergelt, CM, Dalvie, S, Maihofer, AX, Coleman, JR, Bradley, B, Breen, G, Brick, LA, Chen, C-Y, Choi, KW, Duncan, LE, Guffanti, G, Haas, M, Harnal, S, Liberzon, I, Nugent, NR, Provost, AC, Ressler, KJ, Torres, K, Amstadter, AB, Austin, SB, Baker, DG, Bolger, EA, Bryant, RA, Calabrese, JR, Delahanty, DL, Farrer, LA, Feeny, NC, Fiore, JD, Forbes, D, Galea, S, Gautam, A, Gelernter, J, Hammamieh, R, Jett, M, Junglen, AG, Kaufman, ML, Kessler, RC, Khan, A, Kranzler, HR, Lebois, LAM, Marmar, C, Mavissakalian, MR, McFarlane, A, O'Donnell, M, Orcutt, HK, Pietrzak, RH, Risbrough, VB, Roberts, AL, Rothbaum, AO, Roy-Byrne, P, Ruggiero, K, Seligowski, A, Sheerin, CM, Silove, D, Smoller, JW, Stein, MB, Teicher, MH, Ursano, RJ, Van Hooff, M, Winternitz, S, Wolff, JD, Yehuda, R, Zhao, H, Zoellner, LA, Stein, DJ, Koenen, KC, and Nievergelt, CM

Abstract

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be releva

Published
2020

2. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Author

Nievergelt, CM, Maihofer, AX, Klengel, T, Atkinson, EG, Chen, C-Y, Choi, KW, Coleman, JR, Dalvie, S, Duncan, LE, Gelernter, J, Levey, DF, Logue, MW, Polimanti, R, Provost, AC, Ratanatharathorn, A, Stein, MB, Torres, K, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Brglum, AD, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Dale, AM, Daly, MJ, Daskalakis, NP, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Dzubur-Kulenovic, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gelaye, B, Geuze, E, Gillespie, C, Uka, AG, Gordon, SD, Guffanti, G, Hammamieh, R, Harnal, S, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Junglen, AG, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, CE, Linnstaedt, SD, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, J, Marmar, C, Martin, AR, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, McLeay, S, Mehta, D, Milberg, WP, Miller, MW, Morey, RA, Morris, CP, Mors, O, Mortensen, PB, Neale, BM, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Ripke, S, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, K, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Sumner, JA, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Wolff, JD, Yehuda, R, Young, RM, Young, KA, Zhao, H, Zoellner, LA, Liberzon, I, Ressler, KJ, Haas, M, Koenen, KC, Nievergelt, CM, Maihofer, AX, Klengel, T, Atkinson, EG, Chen, C-Y, Choi, KW, Coleman, JR, Dalvie, S, Duncan, LE, Gelernter, J, Levey, DF, Logue, MW, Polimanti, R, Provost, AC, Ratanatharathorn, A, Stein, MB, Torres, K, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Brglum, AD, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Dale, AM, Daly, MJ, Daskalakis, NP, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Dzubur-Kulenovic, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gelaye, B, Geuze, E, Gillespie, C, Uka, AG, Gordon, SD, Guffanti, G, Hammamieh, R, Harnal, S, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Junglen, AG, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, CE, Linnstaedt, SD, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, J, Marmar, C, Martin, AR, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, McLeay, S, Mehta, D, Milberg, WP, Miller, MW, Morey, RA, Morris, CP, Mors, O, Mortensen, PB, Neale, BM, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Ripke, S, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, K, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Sumner, JA, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Wolff, JD, Yehuda, R, Young, RM, Young, KA, Zhao, H, Zoellner, LA, Liberzon, I, Ressler, KJ, Haas, M, and Koenen, KC

Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Published
2019

3. Genomic influences on self-reported childhood maltreatment.

Author

Dalvie S, Maihofer AX, Coleman JRI, Bradley B, Breen G, Brick LA, Chen CY, Choi KW, Duncan LE, Guffanti G, Haas M, Harnal S, Liberzon I, Nugent NR, Provost AC, Ressler KJ, Torres K, Amstadter AB, Bryn Austin S, Baker DG, Bolger EA, Bryant RA, Calabrese JR, Delahanty DL, Farrer LA, Feeny NC, Flory JD, Forbes D, Galea S, Gautam A, Gelernter J, Hammamieh R, Jett M, Junglen AG, Kaufman ML, Kessler RC, Khan A, Kranzler HR, Lebois LAM, Marmar C, Mavissakalian MR, McFarlane A, Donnell MO, Orcutt HK, Pietrzak RH, Risbrough VB, Roberts AL, Rothbaum AO, Roy-Byrne P, Ruggiero K, Seligowski AV, Sheerin CM, Silove D, Smoller JW, Stein MB, Teicher MH, Ursano RJ, Van Hooff M, Winternitz S, Wolff JD, Yehuda R, Zhao H, Zoellner LA, Stein DJ, Koenen KC, and Nievergelt CM

Subjects
Child, Forkhead Transcription Factors, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Repressor Proteins, Self Report, Child Abuse, Stress Disorders, Post-Traumatic
Abstract

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h 2 snp ), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h 2 snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10 -8 , FOXP1; rs10262462, p = 3.24 × 10 -8 , FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h 2 snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r 2  = 0.0025; p = 1.8 × 10 -15 ). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r g  = 0.70, p = 4.65 × 10 -40 ), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

Published
2020
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4. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Author

Nievergelt CM, Maihofer AX, Klengel T, Atkinson EG, Chen CY, Choi KW, Coleman JRI, Dalvie S, Duncan LE, Gelernter J, Levey DF, Logue MW, Polimanti R, Provost AC, Ratanatharathorn A, Stein MB, Torres K, Aiello AE, Almli LM, Amstadter AB, Andersen SB, Andreassen OA, Arbisi PA, Ashley-Koch AE, Austin SB, Avdibegovic E, Babić D, Bækvad-Hansen M, Baker DG, Beckham JC, Bierut LJ, Bisson JI, Boks MP, Bolger EA, Børglum AD, Bradley B, Brashear M, Breen G, Bryant RA, Bustamante AC, Bybjerg-Grauholm J, Calabrese JR, Caldas-de-Almeida JM, Dale AM, Daly MJ, Daskalakis NP, Deckert J, Delahanty DL, Dennis MF, Disner SG, Domschke K, Dzubur-Kulenovic A, Erbes CR, Evans A, Farrer LA, Feeny NC, Flory JD, Forbes D, Franz CE, Galea S, Garrett ME, Gelaye B, Geuze E, Gillespie C, Uka AG, Gordon SD, Guffanti G, Hammamieh R, Harnal S, Hauser MA, Heath AC, Hemmings SMJ, Hougaard DM, Jakovljevic M, Jett M, Johnson EO, Jones I, Jovanovic T, Qin XJ, Junglen AG, Karstoft KI, Kaufman ML, Kessler RC, Khan A, Kimbrel NA, King AP, Koen N, Kranzler HR, Kremen WS, Lawford BR, Lebois LAM, Lewis CE, Linnstaedt SD, Lori A, Lugonja B, Luykx JJ, Lyons MJ, Maples-Keller J, Marmar C, Martin AR, Martin NG, Maurer D, Mavissakalian MR, McFarlane A, McGlinchey RE, McLaughlin KA, McLean SA, McLeay S, Mehta D, Milberg WP, Miller MW, Morey RA, Morris CP, Mors O, Mortensen PB, Neale BM, Nelson EC, Nordentoft M, Norman SB, O'Donnell M, Orcutt HK, Panizzon MS, Peters ES, Peterson AL, Peverill M, Pietrzak RH, Polusny MA, Rice JP, Ripke S, Risbrough VB, Roberts AL, Rothbaum AO, Rothbaum BO, Roy-Byrne P, Ruggiero K, Rung A, Rutten BPF, Saccone NL, Sanchez SE, Schijven D, Seedat S, Seligowski AV, Seng JS, Sheerin CM, Silove D, Smith AK, Smoller JW, Sponheim SR, Stein DJ, Stevens JS, Sumner JA, Teicher MH, Thompson WK, Trapido E, Uddin M, Ursano RJ, van den Heuvel LL, Van Hooff M, Vermetten E, Vinkers CH, Voisey J, Wang Y, Wang Z, Werge T, Williams MA, Williamson DE, Winternitz S, Wolf C, Wolf EJ, Wolff JD, Yehuda R, Young RM, Young KA, Zhao H, Zoellner LA, Liberzon I, Ressler KJ, Haas M, and Koenen KC

Subjects
Black People genetics, Datasets as Topic, Female, Genome-Wide Association Study, Humans, Male, Sex Factors, Veterans statistics & numerical data, White People genetics, Genetic Loci, Genetic Predisposition to Disease, Stress Disorders, Post-Traumatic genetics, Ubiquitin-Protein Ligases genetics
Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Published
2019
Full Text
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5. A multi-level modeling approach examining PTSD symptom reduction during prolonged exposure therapy: moderating effects of number of trauma types experienced, having an HIV-related index trauma, and years since HIV diagnosis among HIV-positive adults.

Author

Junglen AG, Smith BC, Coleman JA, Pacella ML, Boarts JM, Jones T, Feeny NC, Ciesla JA, and Delahanty DL

Subjects
Adult, Female, Humans, Male, Middle Aged, Stress Disorders, Post-Traumatic diagnosis, Stress, Psychological therapy, Time, Treatment Outcome, HIV Infections psychology, Implosive Therapy methods, Stress Disorders, Post-Traumatic psychology, Stress Disorders, Post-Traumatic therapy, Stress, Psychological psychology
Abstract

People living with HIV (PLWH) have extensive interpersonal trauma histories and higher rates of posttraumatic stress disorder (PTSD) than the general population. Prolonged exposure (PE) therapy is efficacious in reducing PTSD across a variety of trauma samples; however, research has not examined factors that influence how PTSD symptoms change during PE for PLWH. Using multi-level modeling, we examined the potential moderating effect of number of previous trauma types experienced, whether the index trauma was HIV-related or not, and years since HIV diagnosis on PTSD symptom reduction during a 10-session PE protocol in a sample of 51 PLWH. In general, PTSD symptoms decreased linearly throughout the PE sessions. Experiencing more previous types of traumatic events was associated with a slower rate of PTSD symptom change. In addition, LOCF analyses found that participants with a non-HIV-related versus HIV-related index trauma had a slower rate of change for PTSD symptoms over the course of PE. However, analyses of raw data decreased this finding to marginal. Years since HIV diagnosis did not impact PTSD symptom change. These results provide a better understanding of how to tailor PE to individual clients and aid clinicians in approximating the rate of symptom alleviation. Specifically, these findings underscore the importance of accounting for trauma history and index trauma type when implementing a treatment plan for PTSD in PLWH.

Published
2017
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