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1. Whole genome sequencing study of identical twins discordant for psychosis

Author: Ormond, Cathal, Ryan, Niamh M., Hedman, Anna M., Cannon, Tyrone D., Sullivan, Patrick F., Gill, Michael, Hultman, Christina, Heron, Elizabeth A., Johansson, Viktoria, Corvin, Aiden, Ormond, Cathal, Ryan, Niamh M., Hedman, Anna M., Cannon, Tyrone D., Sullivan, Patrick F., Gill, Michael, Hultman, Christina, Heron, Elizabeth A., Johansson, Viktoria, and Corvin, Aiden
Abstract: Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.
Published: 2024
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2. Whole genome sequencing study of identical twins discordant for psychosis

Author: Ormond, Cathal, Ryan, Niamh M., Hedman, Anna M., Cannon, Tyrone D., Sullivan, Patrick F., Gill, Michael, Hultman, Christina, Heron, Elizabeth A., Johansson, Viktoria, Corvin, Aiden, Ormond, Cathal, Ryan, Niamh M., Hedman, Anna M., Cannon, Tyrone D., Sullivan, Patrick F., Gill, Michael, Hultman, Christina, Heron, Elizabeth A., Johansson, Viktoria, and Corvin, Aiden
Abstract: Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.
Published: 2024
Full Text: View/download PDF

3. Whole genome sequencing study of identical twins discordant for psychosis

Author: Ormond, Cathal, Ryan, Niamh M., Hedman, Anna M., Cannon, Tyrone D., Sullivan, Patrick F., Gill, Michael, Hultman, Christina, Heron, Elizabeth A., Johansson, Viktoria, Corvin, Aiden, Ormond, Cathal, Ryan, Niamh M., Hedman, Anna M., Cannon, Tyrone D., Sullivan, Patrick F., Gill, Michael, Hultman, Christina, Heron, Elizabeth A., Johansson, Viktoria, and Corvin, Aiden
Abstract: Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.
Published: 2024
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4. Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia

Author: Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., Szatkiewicz, Jin P., Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., and Szatkiewicz, Jin P.
Abstract: Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.
Published: 2023
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5. Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia

Author: Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., Szatkiewicz, Jin P., Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., and Szatkiewicz, Jin P.
Abstract: Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.
Published: 2023
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6. Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia

Author: Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., Szatkiewicz, Jin P., Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., and Szatkiewicz, Jin P.
Abstract: Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.
Published: 2023
Full Text: View/download PDF

7. Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia

Author: Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., Szatkiewicz, Jin P., Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., and Szatkiewicz, Jin P.
Abstract: Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.
Published: 2023
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8. Direct additive genetics and maternal effect contribute to the risk of Tourette disorder

Author: Mahjani, Behrang, Klei, Lambertus, Buxbaum Grice, Ariela S., Larsson, Henrik, Hultman, Christina M., Sandin, Sven, Devlin, Bernie, Buxbaum, Joseph D., Grice, Dorothy E., Mahjani, Behrang, Klei, Lambertus, Buxbaum Grice, Ariela S., Larsson, Henrik, Hultman, Christina M., Sandin, Sven, Devlin, Bernie, Buxbaum, Joseph D., and Grice, Dorothy E.
Abstract: BACKGROUND: Risk for Tourette disorder, and chronic motor or vocal tic disorders (referenced here inclusively as CTD), arise from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD risk, little is known about the role of cross-generational transmission of genetic risk, such as maternal effect, which is not transmitted via the inherited parental genomes. Here, we partition sources of variation on CTD risk into direct additive genetic effect (narrow-sense heritability) and maternal effect. METHODS: The study population consists of 2 522 677 individuals from the Swedish Medical Birth Register, who were born in Sweden between 1 January 1973 and 31 December 2000, and followed for a diagnosis of CTD through 31 December, 2013. We used generalised linear mixed models to partition the liability of CTD into: direct additive genetic effect, genetic maternal effect and environmental maternal effect. RESULTS: We identified 6227 (0.2%) individuals in the birth cohort with a CTD diagnosis. A study of half-siblings showed that maternal half-siblings had twice higher risk of developing a CTD compared with paternal ones. We estimated 60.7% direct additive genetic effect (95% credible interval, 58.5% to 62.4%), 4.8% genetic maternal effect (95% credible interval, 4.4% to 5.1%) and 0.5% environmental maternal effect (95% credible interval, 0.2% to 7%). CONCLUSIONS: Our results demonstrate genetic maternal effect contributes to the risk of CTD. Failure to account for maternal effect results in an incomplete understanding of the genetic risk architecture of CTD, as the risk for CTD is impacted by maternal effect which is above and beyond the risk from transmitted genetic effect., Funding agencies:Mindich Child Health and Development InstituteFriedman Brain InstituteBeatrice and Samuel A. Seaver FoundationMindworks Charitable Lead TrustStanley Center for Psychiatric Research2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation
Published: 2023
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9. Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia

Author: Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., Szatkiewicz, Jin P., Wen, Jia, Trost, Brett, Engchuan, Worrawat, Halvorsen, Matthew, Pallotto, Linda M., Mitina, Aleksandra, Ancalade, NaEshia, Farrell, Martilias, Backstrom, Ian, Guo, Keyi, Pellecchia, Giovanna, Thiruvahindrapuram, Bhooma, Giusti-Rodriguez, Paola, Rosen, Jonathan David, Li, Yun, Won, Hyejung, Magnusson, Patrik K. E., Gyllensten, Ulf B., Bassett, Anne S., Hultman, Christina M., Sullivan, Patrick F., Yuen, Ryan K. C., and Szatkiewicz, Jin P.
Abstract: Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.
Published: 2023
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10. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Author: de Zwarte, Sonja MC, de Zwarte, Sonja MC, Brouwer, Rachel M, Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E, Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth EL, Cahn, Wiepke, Canales-Rodríguez, Erick J, Cannon, Dara M, Cannon, Tyrone D, Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E, Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C, Foley, Sonya F, Frangou, Sophia, Fullerton, Janice M, Glahn, David C, Goghari, Vina M, Goikolea, Jose M, Goldman, Aaron L, Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L, Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon HJ, Houenou, Josselin, Hulshoff Pol, Hilleke E, Hultman, Christina M, Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G, Kane, Fergus, Kempton, Matthew J, Koenis, Marinka MG, Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M, Lenroot, Rhoshel K, Marcelis, Machteld, Mattay, Venkata S, McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B, Moreno, Dolores, Murray, Robin M, Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A, van Os, Jim, Overs, Bronwyn J, Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M, Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S, Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R, Simsek, Esma M, Simsek, Fatma, Soares, Jair C, Sponheim, Scott R, Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R, Whalley, Heather C, Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A, Ching, Christopher RK, Thomopoulos, Sophia I, van Erp, Theo GM, Jahanshad, Neda, Thompson, Paul M, de Zwarte, Sonja MC, de Zwarte, Sonja MC, Brouwer, Rachel M, Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E, Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth EL, Cahn, Wiepke, Canales-Rodríguez, Erick J, Cannon, Dara M, Cannon, Tyrone D, Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E, Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C, Foley, Sonya F, Frangou, Sophia, Fullerton, Janice M, Glahn, David C, Goghari, Vina M, Goikolea, Jose M, Goldman, Aaron L, Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L, Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon HJ, Houenou, Josselin, Hulshoff Pol, Hilleke E, Hultman, Christina M, Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G, Kane, Fergus, Kempton, Matthew J, Koenis, Marinka MG, Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M, Lenroot, Rhoshel K, Marcelis, Machteld, Mattay, Venkata S, McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B, Moreno, Dolores, Murray, Robin M, Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A, van Os, Jim, Overs, Bronwyn J, Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M, Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S, Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R, Simsek, Esma M, Simsek, Fatma, Soares, Jair C, Sponheim, Scott R, Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R, Whalley, Heather C, Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A, Ching, Christopher RK, Thomopoulos, Sophia I, van Erp, Theo GM, Jahanshad, Neda, and Thompson, Paul M
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022

11. Rates of clinically confirmed stressrelated psychiatric disorders among Swedish tsunami survivors : 9-year follow-up

Author: Thordardottir, Edda Bjork, Song, Huan, Arnberg, Filip K., Hauksdottir, Arna, Fang, Fang, Butwicka, Agnieszka, Lichtenstein, Paul, Hultman, Christina M., Valdimarsdottir, Unnur, Thordardottir, Edda Bjork, Song, Huan, Arnberg, Filip K., Hauksdottir, Arna, Fang, Fang, Butwicka, Agnieszka, Lichtenstein, Paul, Hultman, Christina M., and Valdimarsdottir, Unnur
Published: 2022
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12. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Author: Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, Eggan, Kevin, Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, and Eggan, Kevin
Abstract: It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
Published: 2022
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13. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Author: Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, Eggan, Kevin, Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, and Eggan, Kevin
Abstract: It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
Published: 2022
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14. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Author: Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, Eggan, Kevin, Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, and Eggan, Kevin
Abstract: It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
Published: 2022
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15. Rates of Clinically Confirmed Stress-related Psychiatric Disorders Among Swedish Tsunami Survivors : 9-year Follow-up

Author: Thordardottir, Edda Bjork, Song, Huan, Arnberg, Filip K., Hauksdottir, Arna, Fang, Fang, Butwicka, Agnieszka, Lichtenstein, Paul, Hultman, Christina M., Valdimarsdottir, Unnur, Thordardottir, Edda Bjork, Song, Huan, Arnberg, Filip K., Hauksdottir, Arna, Fang, Fang, Butwicka, Agnieszka, Lichtenstein, Paul, Hultman, Christina M., and Valdimarsdottir, Unnur
Published: 2022
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16. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Author: de Zwarte, Sonja MC, de Zwarte, Sonja MC, Brouwer, Rachel M, Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E, Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth EL, Cahn, Wiepke, Canales-Rodríguez, Erick J, Cannon, Dara M, Cannon, Tyrone D, Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E, Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C, Foley, Sonya F, Frangou, Sophia, Fullerton, Janice M, Glahn, David C, Goghari, Vina M, Goikolea, Jose M, Goldman, Aaron L, Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L, Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon HJ, Houenou, Josselin, Hulshoff Pol, Hilleke E, Hultman, Christina M, Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G, Kane, Fergus, Kempton, Matthew J, Koenis, Marinka MG, Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M, Lenroot, Rhoshel K, Marcelis, Machteld, Mattay, Venkata S, McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B, Moreno, Dolores, Murray, Robin M, Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A, van Os, Jim, Overs, Bronwyn J, Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M, Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S, Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R, Simsek, Esma M, Simsek, Fatma, Soares, Jair C, Sponheim, Scott R, Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R, Whalley, Heather C, Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A, Ching, Christopher RK, Thomopoulos, Sophia I, van Erp, Theo GM, Jahanshad, Neda, Thompson, Paul M, de Zwarte, Sonja MC, de Zwarte, Sonja MC, Brouwer, Rachel M, Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E, Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth EL, Cahn, Wiepke, Canales-Rodríguez, Erick J, Cannon, Dara M, Cannon, Tyrone D, Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E, Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C, Foley, Sonya F, Frangou, Sophia, Fullerton, Janice M, Glahn, David C, Goghari, Vina M, Goikolea, Jose M, Goldman, Aaron L, Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L, Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon HJ, Houenou, Josselin, Hulshoff Pol, Hilleke E, Hultman, Christina M, Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G, Kane, Fergus, Kempton, Matthew J, Koenis, Marinka MG, Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M, Lenroot, Rhoshel K, Marcelis, Machteld, Mattay, Venkata S, McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B, Moreno, Dolores, Murray, Robin M, Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A, van Os, Jim, Overs, Bronwyn J, Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M, Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S, Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R, Simsek, Esma M, Simsek, Fatma, Soares, Jair C, Sponheim, Scott R, Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R, Whalley, Heather C, Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A, Ching, Christopher RK, Thomopoulos, Sophia I, van Erp, Theo GM, Jahanshad, Neda, and Thompson, Paul M
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022

17. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., van Haren, Neeltje E. M., de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., and van Haren, Neeltje E. M.
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022
Full Text: View/download PDF

18. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., van Haren, Neeltje E. M., de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., and van Haren, Neeltje E. M.
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022
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19. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., van Haren, Neeltje E. M., de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., and van Haren, Neeltje E. M.
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022
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20. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., van Haren, Neeltje E. M., de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., and van Haren, Neeltje E. M.
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022
Full Text: View/download PDF

21. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., van Haren, Neeltje E. M., de Zwarte, Sonja M. C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E. L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M. G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon-Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R. K., Thomopoulos, Sophia I., van Erp, Theo G. M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., and van Haren, Neeltje E. M.
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022
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22. The impact of educational attainment, intelligence and intellectual disability on schizophrenia:a Swedish population-based register and genetic study

Author: Song, Jie, Yao, Shuyang, Kowalec, Kaarina, Lu, Yi, Sariaslan, Amir, Szatkiewicz, Jin P., Larsson, Henrik, Lichtenstein, Paul, Hultman, Christina M., Sullivan, Patrick F., Song, Jie, Yao, Shuyang, Kowalec, Kaarina, Lu, Yi, Sariaslan, Amir, Szatkiewicz, Jin P., Larsson, Henrik, Lichtenstein, Paul, Hultman, Christina M., and Sullivan, Patrick F.
Abstract: Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.
Published: 2022

23. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Author: Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, Eggan, Kevin, Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, and Eggan, Kevin
Abstract: It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
Published: 2022
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24. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author: Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Curtis, Charles, Nikitina-Zake, Liene, Davidson, Michael, Joa, Inge, Davis, Kenneth L., Yolken, Robert, Murray, Robin M., de Haan, Lieuwe, Legge, Sophie E., Serretti, Alessandro, van Os, Jim, Smoller, Jordan W., Agartz, Ingrid, Alizadeh, Behrooz Z., Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Zai, Clement C., Dikeos, Dimitris, Dinan, Timothy, Henskens, Frans A., Vaaler, Arne, Noto, Cristiano, Nimgaonkar, Vishwajit, Rautanen, Anna, Lehrer, Douglas S., Djurovic, Srdjan, Duan, Jubao, Julià, Antonio, Stahl, Eli A., Zhou, Wei, Vawter, Marquis P., Toncheva, Draga, Webb, Bradley T., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanas Saura, Lourdes, Goldstein, Jacqueline I., Faraone, Stephen V., Lencer, Rebecca, Moreno, Carmen, Bacanu, Silviu A., Fiorentino, Alessia, Calkins, Monica E., Mitjans, Marina, Forstner, Andreas, Nuechterlein, Keith H., Frank, Josef, Tsuang, Debby W., Freimer, Nelson B., Tooney, Paul A., Belangero, Sintia Iole, Weinberger, Daniel R., Fromer, Menachem, Ge,Tian, Adolfsson, Rolf, Hakonarson, Hakon, Zhu, Feng, Frustaci, Alessandra, Nöthen, Markus M., Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Quattrone, Diego, Kähler, Anna K., Kam-Thong, Tony, van Amelsvoort, Therese, Vilella, Elisabet, Molden, Espen, O'Brien, Niamh Louise, Zimprich, Fritz, Kamatani, Yoichiro, Braun, Alice, Melegh, Bela, Pirinen, Matti, Karachanak-Yankova, Sena, Ophoff, Roel A., Kebir, Oussama, Lerer, Bernard, Nordentoft, Merete, Fanous, Ayman H., Reichenberg, Abraham, Li, Miaoxin, Periyasamy, Sathish, Lieberman, Jeffrey, Werge, Thomas, Light, Gregory A., Limborska, Svetlana, Tosato, Sarah, Liu, Chih-Min, Olincy, Ann, Magnusson, Sigurdur, Gareeva, Anna, Bressan, Rodrigo Affonseca, Lönnqvist, Jouko, Roe, Cheryl, Cheng, Wei, Athanasiu, Lavinia, Gutiérrez, Blanca, Harvey, Carol, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Gawlik, Micha, Macek, Milan, Mackinnon, Andrew, Buxbaum, Joseph D., Tura, Gian Battista, Bromet, Evelyn J., Atbaşoğlu, Eşref Cem, Roffman, Joshua L., Magnusson, Patrik K. E., Maher, Brion S., Ota, Vanessa Kiyomi, Paciga, Sara A., Gejman, Pablo V., Arango, Celso, Forti, Marta Di, Maier, Wolfgang, Richards, Alexander L., Malaspina, Dolores, Mallet, Jacques, Metspalu, Andres, Marder, Stephen R., Li, Zhiqiang, Takahashi, Atsushi, Marsal, Sara, Kučinskiene, Zita Ausrele, Suvisaari, Jaana, Martin, Alicia R., Turetsky, Bruce I., Martorell, Lourdes, Palotie, Aarno, Mattheisen, Manuel, Baune, Bernhard T., Saka, Meram C., McCarley, Robert W., Giusti-Rodríguez, Paola, Riley, Brien P., Murphy, Kieran C., Gill, Michael, McDonald, Colm, Bruggeman, Richard, McGrath, John J., Sidorenko, Julia, Medeiros, Helena, Pantelis, Christos, Grove, Jakob, Campion, Dominique, Pato, Carlos N., Svrakic, Dragan M., Üçok, Alp, Glatt, Stephen J., Papadimitriou, George N., Khrunin, Andrey, Straub, Richard E., Parellada, Mara, Buckley, Peter F., Paunio, Tiina, Roth, Julian, Morgan, Vera A., Wildenauer, Dieter B., Ayub, Muhammad, Rothermundt, Matthias, Weiser, Mark, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Børglum, Anders D., Sanjuán, Julio, van Winkel, Ruud, González Peñas, Javier, Yu, Xin, Kim, Sung-Wan, Santoro, Marcos Leite, Benner, Christian, Ikeda, Masashi, Morley, Christopher P., Zeng, Jian, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Voloudakis, Georgios, Yue, Weihua, Seidman, Larry J., Sharp, Sally Isabel, Alptekin, Köksal, Klovins, Janis, Amin, Farooq, Bertolino, Alessandro, Shi, Jianxin, Siever, Larry J., Atkinson, Elizabeth G., Buckner, Randy L., Holmans, Peter A., Rivera, Margarita, Sigurdsson, Engilbert, González-Pinto, Ana, Sim, Kang, Skarabis, Nora, Stroup, T Scott, Slominsky, Petr, Guillin, Olivier, Wang, Shi-Heng, So, Hon-Cheong, Quested, Digby, Sobell, Janet L., Braff, David, Zhang, Wen, Bybjerg-Grauholm, Jonas, Söderman, Erik, Rujescu, Dan, Chambert, Kimberley D., Stain, Helen J., Melle, Ingrid, Carr, Vaughan J, Pocklington, Andrew J., Steen, Nils Eiel, Harwood, Janet, Steixner-Kumar, Agnes A., Gopal, Srihari, Stögmann, Elisabeth, Veijola, Juha, Watanabe, Kyoko, Sham, Pak C., Cahn, Wiepke, Bramon, Elvira, Roussos, Panos, Waddington, John, Perkins, Diana O., Pato, Michele T., Walter, Henrik, Kondratiev, Nikolay, Waterreus, Anna, Al Eissa, Mariam, Bobes, Julio, Golimbet, Vera, Black, Donald W., Als, Thomas D., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Sanders, Alan R., Byerley, William F., Cervilla, Jorge A., Michie, Patricia T., Pfuhlmann, Bruno, Chen, Wei J., Hong, Kyung Sue, O'Neill, F Anthony, Terao, Chikashi, Green, Michael F., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Gülöksüz, Sinan, Freedman, Robert, Albus, Margot, Hayward, Caroline, Pietiläinen, Olli, Herms, Stefan, Hultman, Christina M., Galletly, Cherrie, Gandal, Michael J., Hahn, Eric, Konte, Bettina, Castle, David, Gennarelli, Massimo, Milani, Lili, Hougaard, David M., Hwu, Hai-Gwo, Pulver, Ann E., Jablensky, Assen V., Molina, Esther, Qin, Shengying, McCarroll, Steven A., Moran, Jennifer L., Azevedo, Maria Helena, Gur, Rachel E., Kraft, Julia, Mors, Ole, Catts, Stanley V., Lazzeroni, Laura C., Mortensen, Preben B., Streit, Fabian, Kusumawardhani, Agung, Alexander, Madeline, Godard, Stephanie, Müller-Myhsok, Bertram, Milanova, Vihra, Neil, Amanda L., Cichon, Sven, Giannitelli, Marianna, Cheung, Eric F. C., Kubo, Michiaki, Schwab, Sibylle G., Collier, David A., Williams, Nigel M., Morris, Derek W., Corvin, Aiden, Pimm, Jonathan, Curtis, David, Haroutunian, Vahram, Keller, Matthew C., Vassos, Evangelos, Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Chan, Raymond C. K., Kennedy, James L., Shi, Yongyong, Adams, Mark, Witt, Stephanie H., Khusnutdinova, Elza, Verhage, Matthijs, Xu, Shuhua, Wu, Yang, Kirov, George, Arolt, Volker, Knowles, James A., Moltó, Maria Dolores, Krebs, Marie-Odile, Hartmann, Annette M., Nestadt, Gerald, Wormley, Brandon K., Bass, Nicholas J., Laurent-Levinson, Claudine, Lee, Jimmy, Muntané, Gerard, Porteous, David, Kuzelova-Ptackova, Hana, Lencz, Todd, Subramaniam, Mythily, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Swerdlow, Neal R., Cairns, Murray J., Malhotra, Anil K., Malhotra, Dheeraj, Iyegbe, Conrad, Mondelli, Valeria, Kim, Minsoo, Arrojo, Manuel, Landi, Stefano, McIntosh, Andrew M., Petryshen, Tracey L., Radant, Allen D., Frei, Oleksandr, Mesholam-Gately, Raquelle I., McQuillin, Andrew, Sugar, Catherine A., Menezes, Paulo Rossi, St Clair, David, Meier, Sandra, Powell, John, Chaumette, Boris, Stefansson, Hreinn, Domenici, Enrico, Bonassi, Stefano, Stefánsson, Kári, Wu, Jing Qin, Tsuang, Ming T., Myin-Germeys, Inez, Pellegrino, Renata, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Koopmans, Frank, Kendler, Kenneth S., Chong, Siow Ann, Gur, Ruben C., Ehrenreich, Hannelore, Owen, Michael J., Rietschel, Marcella, Gratten, Jacob, Wray, Naomi R., Hoffmann, Per, Daly, Mark J., Szatkiewicz, Jin P., Huang, Hailiang, Nenadić, Igor, Torretta, Silvia, Escott-Price, Valentina, Neale, Benjamin M., Begemann, Martin, Thibaut, Florence, Agerbo, Esben, Rampino, Antonio, Sullivan, Patrick F., Schulze, Thomas G., Ripke, Stephan, Walters, James T. R., O'Donovan, Michael C., Kučinskas, Vaidutis, Belliveau, Richard A., Bene, Judit, Oh, Sang-Yun, Ta, Thi Minh Tam, Greenwood, Tiffany A., Howrigan, Daniel P., Rapaport, Mark H., Benyamin, Beben, Mowry, Bryan J., Giegling, Ina, Strengman, Eric, Bergen, Sarah E., Silverman, Jeremy M., Blasi, Giuseppe, Cohen, David, Stone, William S., Xu, Zhida, Lee, Phil H., Consoli, Angèle, Kelly, Brian J.., Cordeiro, Quirino, Esko, Tõnu, Costas, Javier, Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Curtis, Charles, Nikitina-Zake, Liene, Davidson, Michael, Joa, Inge, Davis, Kenneth L., Yolken, Robert, Murray, Robin M., de Haan, Lieuwe, Legge, Sophie E., Serretti, Alessandro, van Os, Jim, Smoller, Jordan W., Agartz, Ingrid, Alizadeh, Behrooz Z., Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Zai, Clement C., Dikeos, Dimitris, Dinan, Timothy, Henskens, Frans A., Vaaler, Arne, Noto, Cristiano, Nimgaonkar, Vishwajit, Rautanen, Anna, Lehrer, Douglas S., Djurovic, Srdjan, Duan, Jubao, Julià, Antonio, Stahl, Eli A., Zhou, Wei, Vawter, Marquis P., Toncheva, Draga, Webb, Bradley T., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanas Saura, Lourdes, Goldstein, Jacqueline I., Faraone, Stephen V., Lencer, Rebecca, Moreno, Carmen, Bacanu, Silviu A., Fiorentino, Alessia, Calkins, Monica E., Mitjans, Marina, Forstner, Andreas, Nuechterlein, Keith H., Frank, Josef, Tsuang, Debby W., Freimer, Nelson B., Tooney, Paul A., Belangero, Sintia Iole, Weinberger, Daniel R., Fromer, Menachem, Ge,Tian, Adolfsson, Rolf, Hakonarson, Hakon, Zhu, Feng, Frustaci, Alessandra, Nöthen, Markus M., Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Quattrone, Diego, Kähler, Anna K., Kam-Thong, Tony, van Amelsvoort, Therese, Vilella, Elisabet, Molden, Espen, O'Brien, Niamh Louise, Zimprich, Fritz, Kamatani, Yoichiro, Braun, Alice, Melegh, Bela, Pirinen, Matti, Karachanak-Yankova, Sena, Ophoff, Roel A., Kebir, Oussama, Lerer, Bernard, Nordentoft, Merete, Fanous, Ayman H., Reichenberg, Abraham, Li, Miaoxin, Periyasamy, Sathish, Lieberman, Jeffrey, Werge, Thomas, Light, Gregory A., Limborska, Svetlana, Tosato, Sarah, Liu, Chih-Min, Olincy, Ann, Magnusson, Sigurdur, Gareeva, Anna, Bressan, Rodrigo Affonseca, Lönnqvist, Jouko, Roe, Cheryl, Cheng, Wei, Athanasiu, Lavinia, Gutiérrez, Blanca, Harvey, Carol, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Gawlik, Micha, Macek, Milan, Mackinnon, Andrew, Buxbaum, Joseph D., Tura, Gian Battista, Bromet, Evelyn J., Atbaşoğlu, Eşref Cem, Roffman, Joshua L., Magnusson, Patrik K. E., Maher, Brion S., Ota, Vanessa Kiyomi, Paciga, Sara A., Gejman, Pablo V., Arango, Celso, Forti, Marta Di, Maier, Wolfgang, Richards, Alexander L., Malaspina, Dolores, Mallet, Jacques, Metspalu, Andres, Marder, Stephen R., Li, Zhiqiang, Takahashi, Atsushi, Marsal, Sara, Kučinskiene, Zita Ausrele, Suvisaari, Jaana, Martin, Alicia R., Turetsky, Bruce I., Martorell, Lourdes, Palotie, Aarno, Mattheisen, Manuel, Baune, Bernhard T., Saka, Meram C., McCarley, Robert W., Giusti-Rodríguez, Paola, Riley, Brien P., Murphy, Kieran C., Gill, Michael, McDonald, Colm, Bruggeman, Richard, McGrath, John J., Sidorenko, Julia, Medeiros, Helena, Pantelis, Christos, Grove, Jakob, Campion, Dominique, Pato, Carlos N., Svrakic, Dragan M., Üçok, Alp, Glatt, Stephen J., Papadimitriou, George N., Khrunin, Andrey, Straub, Richard E., Parellada, Mara, Buckley, Peter F., Paunio, Tiina, Roth, Julian, Morgan, Vera A., Wildenauer, Dieter B., Ayub, Muhammad, Rothermundt, Matthias, Weiser, Mark, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Børglum, Anders D., Sanjuán, Julio, van Winkel, Ruud, González Peñas, Javier, Yu, Xin, Kim, Sung-Wan, Santoro, Marcos Leite, Benner, Christian, Ikeda, Masashi, Morley, Christopher P., Zeng, Jian, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Voloudakis, Georgios, Yue, Weihua, Seidman, Larry J., Sharp, Sally Isabel, Alptekin, Köksal, Klovins, Janis, Amin, Farooq, Bertolino, Alessandro, Shi, Jianxin, Siever, Larry J., Atkinson, Elizabeth G., Buckner, Randy L., Holmans, Peter A., Rivera, Margarita, Sigurdsson, Engilbert, González-Pinto, Ana, Sim, Kang, Skarabis, Nora, Stroup, T Scott, Slominsky, Petr, Guillin, Olivier, Wang, Shi-Heng, So, Hon-Cheong, Quested, Digby, Sobell, Janet L., Braff, David, Zhang, Wen, Bybjerg-Grauholm, Jonas, Söderman, Erik, Rujescu, Dan, Chambert, Kimberley D., Stain, Helen J., Melle, Ingrid, Carr, Vaughan J, Pocklington, Andrew J., Steen, Nils Eiel, Harwood, Janet, Steixner-Kumar, Agnes A., Gopal, Srihari, Stögmann, Elisabeth, Veijola, Juha, Watanabe, Kyoko, Sham, Pak C., Cahn, Wiepke, Bramon, Elvira, Roussos, Panos, Waddington, John, Perkins, Diana O., Pato, Michele T., Walter, Henrik, Kondratiev, Nikolay, Waterreus, Anna, Al Eissa, Mariam, Bobes, Julio, Golimbet, Vera, Black, Donald W., Als, Thomas D., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Sanders, Alan R., Byerley, William F., Cervilla, Jorge A., Michie, Patricia T., Pfuhlmann, Bruno, Chen, Wei J., Hong, Kyung Sue, O'Neill, F Anthony, Terao, Chikashi, Green, Michael F., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Gülöksüz, Sinan, Freedman, Robert, Albus, Margot, Hayward, Caroline, Pietiläinen, Olli, Herms, Stefan, Hultman, Christina M., Galletly, Cherrie, Gandal, Michael J., Hahn, Eric, Konte, Bettina, Castle, David, Gennarelli, Massimo, Milani, Lili, Hougaard, David M., Hwu, Hai-Gwo, Pulver, Ann E., Jablensky, Assen V., Molina, Esther, Qin, Shengying, McCarroll, Steven A., Moran, Jennifer L., Azevedo, Maria Helena, Gur, Rachel E., Kraft, Julia, Mors, Ole, Catts, Stanley V., Lazzeroni, Laura C., Mortensen, Preben B., Streit, Fabian, Kusumawardhani, Agung, Alexander, Madeline, Godard, Stephanie, Müller-Myhsok, Bertram, Milanova, Vihra, Neil, Amanda L., Cichon, Sven, Giannitelli, Marianna, Cheung, Eric F. C., Kubo, Michiaki, Schwab, Sibylle G., Collier, David A., Williams, Nigel M., Morris, Derek W., Corvin, Aiden, Pimm, Jonathan, Curtis, David, Haroutunian, Vahram, Keller, Matthew C., Vassos, Evangelos, Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Chan, Raymond C. K., Kennedy, James L., Shi, Yongyong, Adams, Mark, Witt, Stephanie H., Khusnutdinova, Elza, Verhage, Matthijs, Xu, Shuhua, Wu, Yang, Kirov, George, Arolt, Volker, Knowles, James A., Moltó, Maria Dolores, Krebs, Marie-Odile, Hartmann, Annette M., Nestadt, Gerald, Wormley, Brandon K., Bass, Nicholas J., Laurent-Levinson, Claudine, Lee, Jimmy, Muntané, Gerard, Porteous, David, Kuzelova-Ptackova, Hana, Lencz, Todd, Subramaniam, Mythily, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Swerdlow, Neal R., Cairns, Murray J., Malhotra, Anil K., Malhotra, Dheeraj, Iyegbe, Conrad, Mondelli, Valeria, Kim, Minsoo, Arrojo, Manuel, Landi, Stefano, McIntosh, Andrew M., Petryshen, Tracey L., Radant, Allen D., Frei, Oleksandr, Mesholam-Gately, Raquelle I., McQuillin, Andrew, Sugar, Catherine A., Menezes, Paulo Rossi, St Clair, David, Meier, Sandra, Powell, John, Chaumette, Boris, Stefansson, Hreinn, Domenici, Enrico, Bonassi, Stefano, Stefánsson, Kári, Wu, Jing Qin, Tsuang, Ming T., Myin-Germeys, Inez, Pellegrino, Renata, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Koopmans, Frank, Kendler, Kenneth S., Chong, Siow Ann, Gur, Ruben C., Ehrenreich, Hannelore, Owen, Michael J., Rietschel, Marcella, Gratten, Jacob, Wray, Naomi R., Hoffmann, Per, Daly, Mark J., Szatkiewicz, Jin P., Huang, Hailiang, Nenadić, Igor, Torretta, Silvia, Escott-Price, Valentina, Neale, Benjamin M., Begemann, Martin, Thibaut, Florence, Agerbo, Esben, Rampino, Antonio, Sullivan, Patrick F., Schulze, Thomas G., Ripke, Stephan, Walters, James T. R., O'Donovan, Michael C., Kučinskas, Vaidutis, Belliveau, Richard A., Bene, Judit, Oh, Sang-Yun, Ta, Thi Minh Tam, Greenwood, Tiffany A., Howrigan, Daniel P., Rapaport, Mark H., Benyamin, Beben, Mowry, Bryan J., Giegling, Ina, Strengman, Eric, Bergen, Sarah E., Silverman, Jeremy M., Blasi, Giuseppe, Cohen, David, Stone, William S., Xu, Zhida, Lee, Phil H., Consoli, Angèle, Kelly, Brian J.., Cordeiro, Quirino, Esko, Tõnu, and Costas, Javier
Abstract: Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
Published: 2022

25. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

Author: Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, Eggan, Kevin, Nehme, Ralda, Pietiläinen, Olli, Artomov, Mykyta, Tegtmeyer, Matthew, Valakh, Vera, Lehtonen, Leevi, Bell, Christina, Singh, Tarjinder, Trehan, Aditi, Sherwood, John, Manning, Danielle, Peirent, Emily, Malik, Rhea, Guss, Ellen J., Hawes, Derek, Beccard, Amanda, Bara, Anne M., Hazelbaker, Dane Z., Zuccaro, Emanuela, Genovese, Giulio, Loboda, Alexander A., Neumann, Anna, Lilliehook, Christina, Kuismin, Outi, Hamalainen, Eija, Kurki, Mitja, Hultman, Christina M., Kähler, Anna K., Paulo, Joao A., Ganna, Andrea, Madison, Jon, Cohen, Bruce, McPhie, Donna, Adolfsson, Rolf, Perlis, Roy, Dolmetsch, Ricardo, Farhi, Samouil, McCarroll, Steven, Hyman, Steven, Neale, Ben, Barrett, Lindy E., Harper, Wade, Palotie, Aarno, Daly, Mark, and Eggan, Kevin
Abstract: It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
Published: 2022
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26. The impact of educational attainment, intelligence and intellectual disability on schizophrenia:a Swedish population-based register and genetic study

Author: Song, Jie, Yao, Shuyang, Kowalec, Kaarina, Lu, Yi, Sariaslan, Amir, Szatkiewicz, Jin P., Larsson, Henrik, Lichtenstein, Paul, Hultman, Christina M., Sullivan, Patrick F., Song, Jie, Yao, Shuyang, Kowalec, Kaarina, Lu, Yi, Sariaslan, Amir, Szatkiewicz, Jin P., Larsson, Henrik, Lichtenstein, Paul, Hultman, Christina M., and Sullivan, Patrick F.
Abstract: Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.
Published: 2022

27. Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

Author: de Zwarte, Sonja M.C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E.L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M.G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R.K., Thomopoulos, Sophia I., van Erp, Theo G.M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., van Haren, Neeltje E.M., de Zwarte, Sonja M.C., Brouwer, Rachel M., Agartz, Ingrid, Alda, Martin, Alonso-Lana, Silvia, Bearden, Carrie E., Bertolino, Alessandro, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth E.L., Cahn, Wiepke, Canales-Rodríguez, Erick J., Cannon, Dara M., Cannon, Tyrone D., Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, del Mar Bonnin, Caterina, Demro, Caroline, Di Giorgio, Annabella, Doucet, Gaelle E., Eker, Mehmet Cagdas, Erk, Susanne, Fatjó-Vilas, Mar, Fears, Scott C., Foley, Sonya F., Frangou, Sophia, Fullerton, Janice M., Glahn, David C., Goghari, Vina M., Goikolea, Jose M., Goldman, Aaron L., Gonul, Ali Saffet, Gruber, Oliver, Hajek, Tomas, Hawkins, Emma L., Heinz, Andreas, Hidiroglu Ongun, Ceren, Hillegers, Manon H.J., Houenou, Josselin, Hulshoff Pol, Hilleke E., Hultman, Christina M., Ingvar, Martin, Johansson, Viktoria, Jönsson, Erik G., Kane, Fergus, Kempton, Matthew J., Koenis, Marinka M.G., Kopecek, Miloslav, Krämer, Bernd, Lawrie, Stephen M., Lenroot, Rhoshel K., Marcelis, Machteld, Mattay, Venkata S., McDonald, Colm, Meyer-Lindenberg, Andreas, Michielse, Stijn, Mitchell, Philip B., Moreno, Dolores, Murray, Robin M., Mwangi, Benson, Nabulsi, Leila, Newport, Jason, Olman, Cheryl A., van Os, Jim, Overs, Bronwyn J., Ozerdem, Aysegul, Pergola, Giulio, Picchioni, Marco M., Piguet, Camille, Pomarol-Clotet, Edith, Radua, Joaquim, Ramsay, Ian S., Richter, Anja, Roberts, Gloria, Salvador, Raymond, Saricicek Aydogan, Aybala, Sarró, Salvador, Schofield, Peter R., Simsek, Esma M., Simsek, Fatma, Soares, Jair C., Sponheim, Scott R., Sugranyes, Gisela, Toulopoulou, Timothea, Tronchin, Giulia, Vieta, Eduard, Walter, Henrik, Weinberger, Daniel R., Whalley, Heather C., Wu, Mon Ju, Yalin, Nefize, Andreassen, Ole A., Ching, Christopher R.K., Thomopoulos, Sophia I., van Erp, Theo G.M., Jahanshad, Neda, Thompson, Paul M., Kahn, René S., and van Haren, Neeltje E.M.
Abstract: First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = −0.42, p = 3 × 10−5), with weak evidence of IQ reductions among BD-FDRs (d = −0.23, p =.045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Published: 2022

28. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Author: Jia, Xiaoming, Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, Scott, Laura J, Jia, Xiaoming, Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, and Scott, Laura J
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
Published: 2021

29. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Mullins, Niamh, Forstner, Andreas J., O'Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R., I, Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Borte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Baekvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Pedersen, Carsten Bocker, Boen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsashagen, Torbjorn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisen, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Pedersen, Marianne Giortz, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, Jose, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stephane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Muhleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Loohuis, Loes M. Olde, Oruc, Lilijana, Papiol, Sergi, Pardinas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sanchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Hansen, Christine Soholm, Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Swiatkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Borglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tonu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen, V, Jones, Ian, Jones, Lisa A., Kahn, Rene S., Kelsoe, John R., Kirov, George, Landen, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Muller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nothen, Markus M., ODonovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribases, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, JohnAnker, Biernacka, Joanna M., Nurnberger, John, I, Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., Andreassen, Ole A., Mullins, Niamh, Forstner, Andreas J., O'Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R., I, Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Borte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Baekvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Pedersen, Carsten Bocker, Boen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsashagen, Torbjorn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisen, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Pedersen, Marianne Giortz, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, Jose, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stephane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Muhleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Loohuis, Loes M. Olde, Oruc, Lilijana, Papiol, Sergi, Pardinas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sanchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Hansen, Christine Soholm, Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Swiatkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Borglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tonu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen, V, Jones, Ian, Jones, Lisa A., Kahn, Rene S., Kelsoe, John R., Kirov, George, Landen, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Muller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nothen, Markus M., ODonovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribases, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, JohnAnker, Biernacka, Joanna M., Nurnberger, John, I, Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
Published: 2021

30. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 x 10(-4) were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 x 10(-7)). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021

31. Mediterranean diet and depression : a population-based cohort study

Author: Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, Sandin, Sven, Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, and Sandin, Sven
Abstract: Background Depression imposes immense public health burden, demonstrating an urgent need of the identification of modifiable risk factors. Only a few cohort studies have analyzed the association between Mediterranean dietary pattern (MDP) and depression but with mixed results. We examined the impact of MDP on clinically ascertained depression in a large population-based dataset. Methods In 1991/92, detailed information on diet, using a food frequency questionnaire, and potential confounding factors (body weight, height, educational attainment, smoking, previous diabetes and hypertension, and physical activity) was collected, in a random sample of 49,261 Swedish women aged 29-49. Adherence to MDP was calculated. Clinical depression was extracted from the National Patient Register. Study participants were followed up through 2012. Results During an average follow-up of 20.4 years, 1677 incident cases of depression were diagnosed. We observed a lower risk of depression for medium (score 4-5) and high (6-9) adherence to MDP, compared with low (0-3) adherence (Medium: hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.81-1.00; High: HR = 0.82, 95%CI = 0.71-0.94). Per unit increase of adherence, the risk of depression was reduced by 5% (HR = 0.95, 95%CI = 0.92-0.98). The association became stronger when restricting to severe form of depression (HR = 0.51, 95%CI = 0.33-0.76). The HRs were higher from age 50 onward both over the first and the second 10-year follow-up period, compared with before age 50, indicating stronger association with increasing age. Results remained after extensive sensitivity analyses. Conclusion Higher adherence to a Mediterranean diet at middle age was associated with a lower risk of depression later in life among Swedish women., Funding Agencies|Karolinska InstituteKarolinska Institutet; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-01088]; Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2017-00531]; Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology)
Published: 2021
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32. The association between family history and genomic burden with schizophrenia mortality : a Swedish population-based register and genetic sample study

Author: Kowalec, Kaarina, Lu, Yi, Song, Jie, Dalman, Christina, Hultman, Christina M., Larsson, Henrik, Lichtenstein, Paul, Sullivan, Patrick F., Kowalec, Kaarina, Lu, Yi, Song, Jie, Dalman, Christina, Hultman, Christina M., Larsson, Henrik, Lichtenstein, Paul, and Sullivan, Patrick F.
Abstract: Individuals with schizophrenia (SCZ) have a 2-3-fold higher risk of mortality than the general population. Heritability of mortality in psychiatric disorders has been proposed; however, few have investigated SCZ family history and genetic variation, with all-cause and specific causes of death. We aimed to identify correlates of SCZ mortality using genetic epidemiological and genetic modelling in two samples: a Swedish national population sample and a genotyped subsample. In the Swedish national population sample followed from the first SCZ treatment contact until emigration, death or end of the follow-up, we investigated a standardised measure of SCZ family history. In a subgroup with comprehensive genetic data, we investigated the impact of common and rare genetic variation. Cox proportional hazards regression was used to estimate the association between various factors and mortality (all and specific causes). A total of 13727 SCZ cases fulfilled criteria for the population-based analyses (1268 deaths, 9.2%). The genomic subset contained 4991 cases (1353 deaths, 27.1%). Somatic mutations associated with clonal hematopoiesis with unknown drivers were associated with all-cause mortality (HR 1.77, 95% CI: 1.26-2.49). No other heritable measures were associated with all-cause mortality nor with any specific causes of death. Future studies in larger, comparable cohorts are warranted to further understand the association between hereditary measures and mortality in SCZ., Funding Agencies:European Union's Horizon 2020 Research and Innovation programme under the Marie Skodowska-Curie grant agreement 793530Government of Canada Banting Postdoctoral Fellowship Programme University of Manitoba United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) R01 MH77139 U01 MH109528 R01 MH077139
Published: 2021
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33. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021
Full Text: View/download PDF

34. Mediterranean diet and depression : a population-based cohort study

Author: Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, Sandin, Sven, Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, and Sandin, Sven
Abstract: Background Depression imposes immense public health burden, demonstrating an urgent need of the identification of modifiable risk factors. Only a few cohort studies have analyzed the association between Mediterranean dietary pattern (MDP) and depression but with mixed results. We examined the impact of MDP on clinically ascertained depression in a large population-based dataset. Methods In 1991/92, detailed information on diet, using a food frequency questionnaire, and potential confounding factors (body weight, height, educational attainment, smoking, previous diabetes and hypertension, and physical activity) was collected, in a random sample of 49,261 Swedish women aged 29-49. Adherence to MDP was calculated. Clinical depression was extracted from the National Patient Register. Study participants were followed up through 2012. Results During an average follow-up of 20.4 years, 1677 incident cases of depression were diagnosed. We observed a lower risk of depression for medium (score 4-5) and high (6-9) adherence to MDP, compared with low (0-3) adherence (Medium: hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.81-1.00; High: HR = 0.82, 95%CI = 0.71-0.94). Per unit increase of adherence, the risk of depression was reduced by 5% (HR = 0.95, 95%CI = 0.92-0.98). The association became stronger when restricting to severe form of depression (HR = 0.51, 95%CI = 0.33-0.76). The HRs were higher from age 50 onward both over the first and the second 10-year follow-up period, compared with before age 50, indicating stronger association with increasing age. Results remained after extensive sensitivity analyses. Conclusion Higher adherence to a Mediterranean diet at middle age was associated with a lower risk of depression later in life among Swedish women., Funding Agencies|Karolinska InstituteKarolinska Institutet; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-01088]; Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2017-00531]; Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology)
Published: 2021
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35. Mediterranean diet and depression : a population-based cohort study

Author: Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, Sandin, Sven, Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, and Sandin, Sven
Abstract: Background Depression imposes immense public health burden, demonstrating an urgent need of the identification of modifiable risk factors. Only a few cohort studies have analyzed the association between Mediterranean dietary pattern (MDP) and depression but with mixed results. We examined the impact of MDP on clinically ascertained depression in a large population-based dataset. Methods In 1991/92, detailed information on diet, using a food frequency questionnaire, and potential confounding factors (body weight, height, educational attainment, smoking, previous diabetes and hypertension, and physical activity) was collected, in a random sample of 49,261 Swedish women aged 29-49. Adherence to MDP was calculated. Clinical depression was extracted from the National Patient Register. Study participants were followed up through 2012. Results During an average follow-up of 20.4 years, 1677 incident cases of depression were diagnosed. We observed a lower risk of depression for medium (score 4-5) and high (6-9) adherence to MDP, compared with low (0-3) adherence (Medium: hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.81-1.00; High: HR = 0.82, 95%CI = 0.71-0.94). Per unit increase of adherence, the risk of depression was reduced by 5% (HR = 0.95, 95%CI = 0.92-0.98). The association became stronger when restricting to severe form of depression (HR = 0.51, 95%CI = 0.33-0.76). The HRs were higher from age 50 onward both over the first and the second 10-year follow-up period, compared with before age 50, indicating stronger association with increasing age. Results remained after extensive sensitivity analyses. Conclusion Higher adherence to a Mediterranean diet at middle age was associated with a lower risk of depression later in life among Swedish women., Funding Agencies|Karolinska InstituteKarolinska Institutet; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-01088]; Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2017-00531]; Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology)
Published: 2021
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36. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Author: Jia, Xiaoming, Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, Scott, Laura J, Jia, Xiaoming, Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, and Scott, Laura J
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
Published: 2021

37. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., Andreassen, Ole A., Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2021
Full Text: View/download PDF

38. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author: Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Goncalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Jureus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zollner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., Scott, Laura J., Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Goncalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Jureus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zollner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., and Scott, Laura J.
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., Errata: Jia, X., Goes, F.S., Locke, A.E. et al. Correction to: Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder. Molecular Psychiatry (2021). DOI: 10.1038/s41380-021-01063-8
Published: 2021
Full Text: View/download PDF

39. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author: Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Goncalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Jureus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zollner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., Scott, Laura J., Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Goncalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Jureus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zollner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., and Scott, Laura J.
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., Errata: Jia, X., Goes, F.S., Locke, A.E. et al. Correction to: Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder. Molecular Psychiatry (2021). DOI: 10.1038/s41380-021-01063-8
Published: 2021
Full Text: View/download PDF

40. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author: Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Goncalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Jureus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zollner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., Scott, Laura J., Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Goncalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Jureus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zollner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., and Scott, Laura J.
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., Errata: Jia, X., Goes, F.S., Locke, A.E. et al. Correction to: Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder. Molecular Psychiatry (2021). DOI: 10.1038/s41380-021-01063-8
Published: 2021
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41. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 x 10(-4) were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 x 10(-7)). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021

42. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author: Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., Mill, Jonathan, Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., and Mill, Jonathan
Abstract: We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Published: 2021
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43. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author: Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., Mill, Jonathan, Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., and Mill, Jonathan
Abstract: We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Published: 2021
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44. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author: Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., Mill, Jonathan, Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., and Mill, Jonathan
Abstract: We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Published: 2021
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45. Mediterranean diet and depression : a population-based cohort study

Author: Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, Sandin, Sven, Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, and Sandin, Sven
Abstract: Background Depression imposes immense public health burden, demonstrating an urgent need of the identification of modifiable risk factors. Only a few cohort studies have analyzed the association between Mediterranean dietary pattern (MDP) and depression but with mixed results. We examined the impact of MDP on clinically ascertained depression in a large population-based dataset. Methods In 1991/92, detailed information on diet, using a food frequency questionnaire, and potential confounding factors (body weight, height, educational attainment, smoking, previous diabetes and hypertension, and physical activity) was collected, in a random sample of 49,261 Swedish women aged 29-49. Adherence to MDP was calculated. Clinical depression was extracted from the National Patient Register. Study participants were followed up through 2012. Results During an average follow-up of 20.4 years, 1677 incident cases of depression were diagnosed. We observed a lower risk of depression for medium (score 4-5) and high (6-9) adherence to MDP, compared with low (0-3) adherence (Medium: hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.81-1.00; High: HR = 0.82, 95%CI = 0.71-0.94). Per unit increase of adherence, the risk of depression was reduced by 5% (HR = 0.95, 95%CI = 0.92-0.98). The association became stronger when restricting to severe form of depression (HR = 0.51, 95%CI = 0.33-0.76). The HRs were higher from age 50 onward both over the first and the second 10-year follow-up period, compared with before age 50, indicating stronger association with increasing age. Results remained after extensive sensitivity analyses. Conclusion Higher adherence to a Mediterranean diet at middle age was associated with a lower risk of depression later in life among Swedish women., Funding Agencies|Karolinska InstituteKarolinska Institutet; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-01088]; Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2017-00531]; Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology)
Published: 2021
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46. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author: Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., Mill, Jonathan, Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., and Mill, Jonathan
Abstract: We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Published: 2021
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47. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author: Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., Mill, Jonathan, Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C., Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David Andrew, Murray, Robin M., Schalkwyk, Leonard S., and Mill, Jonathan
Abstract: We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Published: 2021
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48. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Published: 2021

49. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Mullins, Niamh, Forstner, Andreas J., O'Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R., I, Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Borte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Baekvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Pedersen, Carsten Bocker, Boen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsashagen, Torbjorn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisen, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Pedersen, Marianne Giortz, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, Jose, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stephane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Muhleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Loohuis, Loes M. Olde, Oruc, Lilijana, Papiol, Sergi, Pardinas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sanchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Hansen, Christine Soholm, Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Swiatkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Borglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tonu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen, V, Jones, Ian, Jones, Lisa A., Kahn, Rene S., Kelsoe, John R., Kirov, George, Landen, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Muller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nothen, Markus M., ODonovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribases, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, JohnAnker, Biernacka, Joanna M., Nurnberger, John, I, Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., Andreassen, Ole A., Mullins, Niamh, Forstner, Andreas J., O'Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R., I, Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Borte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Baekvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Pedersen, Carsten Bocker, Boen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsashagen, Torbjorn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisen, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Pedersen, Marianne Giortz, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, Jose, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stephane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Muhleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Loohuis, Loes M. Olde, Oruc, Lilijana, Papiol, Sergi, Pardinas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sanchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Hansen, Christine Soholm, Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Swiatkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Borglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tonu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen, V, Jones, Ian, Jones, Lisa A., Kahn, Rene S., Kelsoe, John R., Kirov, George, Landen, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Muller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nothen, Markus M., ODonovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribases, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, JohnAnker, Biernacka, Joanna M., Nurnberger, John, I, Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
Published: 2021

50. Mediterranean diet and depression : a population-based cohort study

Author: Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, Sandin, Sven, Yin, Weiyao, Löf, Marie, Chen, Ruoqing, Hultman, Christina M., Fang, Fang, and Sandin, Sven
Abstract: Background Depression imposes immense public health burden, demonstrating an urgent need of the identification of modifiable risk factors. Only a few cohort studies have analyzed the association between Mediterranean dietary pattern (MDP) and depression but with mixed results. We examined the impact of MDP on clinically ascertained depression in a large population-based dataset. Methods In 1991/92, detailed information on diet, using a food frequency questionnaire, and potential confounding factors (body weight, height, educational attainment, smoking, previous diabetes and hypertension, and physical activity) was collected, in a random sample of 49,261 Swedish women aged 29-49. Adherence to MDP was calculated. Clinical depression was extracted from the National Patient Register. Study participants were followed up through 2012. Results During an average follow-up of 20.4 years, 1677 incident cases of depression were diagnosed. We observed a lower risk of depression for medium (score 4-5) and high (6-9) adherence to MDP, compared with low (0-3) adherence (Medium: hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.81-1.00; High: HR = 0.82, 95%CI = 0.71-0.94). Per unit increase of adherence, the risk of depression was reduced by 5% (HR = 0.95, 95%CI = 0.92-0.98). The association became stronger when restricting to severe form of depression (HR = 0.51, 95%CI = 0.33-0.76). The HRs were higher from age 50 onward both over the first and the second 10-year follow-up period, compared with before age 50, indicating stronger association with increasing age. Results remained after extensive sensitivity analyses. Conclusion Higher adherence to a Mediterranean diet at middle age was associated with a lower risk of depression later in life among Swedish women., Funding Agencies|Karolinska InstituteKarolinska Institutet; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-01088]; Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [2017-00531]; Karolinska Institutet (Senior Researcher Award and Strategic Research Area in Epidemiology)
Published: 2021
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