Familial Psychosis Associated With a Missense Mutation at MACF1 Gene Combined With the Rare Duplications DUP3p26.3 and DUP16q23.3, Affecting the CNTN6 and CDH13 Genes

Psychosis is a highly heritable and heterogeneous psychiatric condition. Its genetic architecture is thought to be the result of the joint effect of common and rare variants. Families with high prevalence are an interesting approach to shed light on the rare variant's contribution without the need of collecting large cohorts. To unravel the genomic architecture of a family enriched for psychosis, with four affected individuals, we applied a system genomic approach based on karyotyping, genotyping by whole-exome sequencing to search for rare single nucleotide variants (SNVs) and SNP array to search for copy-number variants (CNVs). We identified a rare non-synonymous variant, g.39914279 C \textgreater G, in the MACF1 gene, segregating with psychosis. Rare variants in the MACF1 gene have been previously detected in SCZ patients. Besides, two rare CNVs, DUP3p26.3 and DUP16q23.3, were also identified in the family affecting relevant genes (CNTN6 and CDH13, respectively). We hypothesize that the co-segregation of these duplications with the rare variant g.39914279 C \textgreater G of MACF1 gene precipitated with schizophrenia and schizoaffective disorder

Blue Genes : Synopsis of the workshop organized by ICM-CSIC and BAU to increase engagement and collaboration for Our Ocean and Waters

7 pagesOn October 27th, 2022, the Institut de Ciències del Mar (ICM-CSIC), a marine research institution located in Barcelona, and the College of Arts & Design of Barcelona (BAU), a higher-education centre specialized in arts and design, co-organized the first Blue Genes meeting. This meeting took place virtually in a 3-hour workshop format and counted with more than 50 participants from different locations. Its main goal was to explore in a co-creative way how to reinforce and empower the engagement of people, particularly teenagers and young adults, with our Ocean and Waters and increase networking and collaboration. This meeting was the first workshop of a series of planned activities under the Blue Genes initiativePeer reviewe

Disentangling the genomic architecture of psychosis in families with high prevalence through system genomic approaches

[eng] Psychotic disorders as schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders with overlapping symptomatology, high heterogeneity, and shared genetic susceptibility. Different phenotype definitions, for example, the presence of psychotic symptoms, have been proposed to reduce the phenotypic heterogeneity imposed by clinical classifications. The current consensus assumes that the genetic architecture of psychosis is the result of the combined effect of common and rare variants. Identifying rare variants associated with the disease is complicated at a population level. Therefore, analyzing families with a high prevalence of psychosis is an interesting approach to identify highly penetrant variants. In this thesis, in an attempt to disentangle the genomic architecture of psychosis, two families with high prevalence were analyzed. Two phenotypes were defined: (i) Wide, referred to any psychiatric disorder, and (ii) Narrow, referred to disorders presenting with psychosis. Family 1 of Majorcan origin had five narrow individuals. Family 2, a large family from Alpujarras, Granada (Andalucía), a region with a high prevalence of psychosis, had 42 wide subjects, 27 of which were narrow. In both Families, system genomic approaches were applied, based on karyotyping (Family 1; n = 2 and Family 2; n = 3), genotyping by SNP array (Family 1; n = 13 and Family 2; n = 33), and whole-exome (WES; Family 1; n = 5 and Family 2; n = 4) and whole-genome sequencing (WGS; Family 2; n = 12), to search for rare single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) segregating with the phenotype. In both Families, we performed genome-wide linkage analysis, family-based association analysis, and polygenic risk score estimates. In Family 1, two different genomic architectures were identified in the two family branches. In the first branch, psychosis is the result of the combined effect of two duplications DUP3p26.3 (CNTN6) and DUP16p23.3 (CDH13), and two rare missense variants in MACF1 and GLI2 genes. Other rare missense variants identified in the family may also play an important role (VPS8, TNR, and GJA1). In the other branch, psychosis seems to precipitate due to two deletions DEL3q28 (OSTN/UTS2B) and DEL13q31.2. Several missense variants may also play a role in this branch (SERPINI1, CCDC141, and TNR). Moreover, four suggestive linkage regions (LOD scores > 1) were identified in Family 1 (1q41-42.3; 3q26.2-27.3; 4q34.3-35.1 and 11q21-23.3). Comprehensive analysis of these regions combined with the shared genes harboring rare variants evidenced enrichment for biological processes associated with psychotic disorders, such as neuronal organization and development. 2 The genomic architecture of psychosis in Family 2 is associated with the region 9q31.3-q33.2, with a significant linkage (LODwide = 4.11, LODnarrow = 3.07). This region contains five candidate genes (ASTN2, BRINP1, C5, TLR4, and TRIM32) previously associated with major mental disorders. Not a single rare variant shared among all affected individuals was identified in this region. Contributing to the genomic architecture we also found several rare missense variants (CSMD1, HHAT, PALB2, SHANK2, RTN4R, TNC, CDK5RAP2, GSN, C5, KDM4C, and ARHGAP19) and structural variants (DUP3q29, DUP4q35.2, DUP9p24.1, DUP11p14.2, DUP18q22.1, DUP22q11.23, DEL6p21.33, DEL8p23.2, and DEL12q14.1) plus other suggestive regions in both phenotype analyses (LOD score > 1). All those regions were enriched for genes involved in synapsis, the immune system, and the cytoskeleton. The results of this thesis confirm that psychosis is highly heterogeneous and evidence the inherent difficulties for understanding its genetic architecture. Nevertheless, they also strengthen the convenience of combining different system genomic approaches to identify genetic variants and potential gene candidates for understanding its genetic etiology.[cat] Els trastorns psicòtics com l’esquizofrènia i el trastorn bipolar presenten una elevada heretabilitat, simptomatologia superposada, elevada heterogeneïtat i susceptibilitat genètica compartida. S’han proposat diferent definicions fenotípiques, com per exemple, la presència de símptomes psicòtics, per reduir-ne l’heterogeneitat fenotípica. A dia d’avui hi ha un ampli consens en que l’arquitectura genètica de la psicosi és el resultat de l’efecte combinat de variants comunes i rares. La identificació de variants rares associades a la malaltia és complicada a nivell poblacional, pel que l’anàlisi de famílies amb alta prevalença és una aproximació prometedora per identificar variants d’elevada penetrància. En aquesta tesi es van analitzar dues famílies amb alta prevalença de la malaltia amb l’objectiu de comprendre millor l’arquitectura genètica de la psicosi. Es van definir dos fenotips: (i) “l’ample”, que incloïa qualsevol trastorn psiquiàtric, i (ii) el “restringit”, que incloïa trastorns que cursen amb psicosi. La família 1, d'origen mallorquí, tenia cinc individus amb fenotip “restringit”. Per contra, la família 2 de les Alpujarras (Granada), una regió amb alta prevalença de la malaltia, tenia 42 individus amb fenotip “ample”, dels quals 27 presentaven símptomes psicòtics. En ambdues famílies, es van aplicar tècniques pròpies de la genòmica de sistemes, cariotip (família 1; n = 2 i família 2; n = 3), genotipat per SNP array (família 1; n = 13 i família 2; n = 33), i seqüenciació de l’exoma (família 1; n = 5 i família 2; n = 4) i genoma complet (família 2; n = 12), amb l’objectiu de trobar variants rares, polimorfismes de nucleòtid únic i variacions en el número de còpies, que segreguessin amb el fenotip. En ambdues famílies, vam realitzar anàlisis de lligament, d’associació i estimacions de risc genètic. A la família 1, es van identificar dues arquitectures genètiques diferents en cada una de les dues branques familiars. A la primera, la psicosi és el resultat de l’efecte combinat de dues duplicacions, DUP3p26.3 (CNTN6) i DUP16p23.3 (CDH13), i de dues variants rares amb error de sentit en MACF1 i GLI2. Altres variants rares identificades també podrien estar jugant-hi un paper important (VPS8, TNR i GJA1). A l’altra branca, la psicosi sembla ser el resultat de dues delecions: DEL3q28 (OSTN/UTS2B) i DEL13q31.2. També en aquesta branca hi ha diverses variants rares que poden participar en el fenotip (SERPINI1, CCDC141 i TNR). A més, es van identificar quatre regions (1q41-42.3; 3q26.2-27.3; 4q34.3-35.1 i 11q21-23.3) suggestives de lligament (puntuacions LOD > 1). L’anàlisi d’aquestes regions i dels 4 gens portadors de variants rares va mostrar un enriquiment en processos biològics rellevants per la malaltia, com l’organització i el desenvolupament neuronal. L’arquitectura genètica de la família 2 s’associa a la regió 9q31.3-q33.2, amb un resultat de lligament significatiu (LODwide = 4.11, LODnarrow = 3.07). Aquesta regió conté cinc gens prèviament associats amb trastorns mentals (ASTN2, BRINP1, C5, TLR4 i TRIM32). No s’hi va trobar cap variant rara compartida entre tots els individus afectes. D’altres variants rares també poden estar contribuint a l’arquitectura genètica de la família incloent variants amb error de sentit (CSMD1, HHAT, PALB2, SHANK2, RTN4R, TNC, CDK5RAP2, GSN, C5, KDM4C i ARHGAP19), variants estructurals (DUP3q29, DUP4q35.2, DUP9p24.1, DUP11p14.2, DUP18q22.1, DUP22q11.23, DEL6p21.33, DEL8p23.2 i DEL12q14.1), i d’altres regions suggestives identificades en l’anàlisi de lligament d’ambdós fenotips (puntuació LOD > 1). Aquestes regions estan enriquides en gens implicats en la sinapsi, el sistema immunitari i el citoesquelet. Els resultats d’aquesta tesi confirmen d’una banda l’elevada heterogeneïtat de la psicosi i de l’altre les dificultats inherents per entendre la seva arquitectura genètica. Així mateix, també donen suport a les aproximacions basades en la genòmica de sistemes que permeten identificar variants genètiques i possibles gens candidats.[spa] Los trastornos psicóticos como la esquizofrenia y el trastorno bipolar tienen una elevada heredabilidad, sintomatología superpuesta, elevada heterogeneidad y susceptibilidad genética compartida. Se han propuesto diferentes definiciones fenotípicas, por ejemplo, la presencia de síntomas psicóticos, para reducir la heterogeneidad fenotípica. Actualmente se acepta ampliamente que la arquitectura genética de la psicosis es el resultado del efecto combinado de variantes comunes y raras. La identificación de variantes raras es complicada a nivel poblacional, por lo que el análisis de familias con alta prevalencia de psicosis es una aproximación interesante para identificar variantes penetrantes. En esta tesis, se analizaron dos familias con alta prevalencia con el objetivo de comprender la arquitectura genómica de la psicosis. Se definieron dos fenotipos: (i) “Amplio”, incluyendo cualquier trastorno psiquiátrico, y (ii) “Estrecho”, referido a los trastornos que cursan con psicosis. La familia 1 de origen mallorquín tenía cinco individuos psicóticos. La familia 2, una amplia familia de las Alpujarras (Granada), una región con una alta prevalencia de psicosis, tenía 42 individuos con fenotipo psiquiátrico, de los cuales 27 eran psicóticos. En ambas familias, se aplicaron aproximaciones de la genómica de sistemas, cariotipo (Familia 1; n = 2 y Familia 2; n = 3), genotipado por SNP array (Familia 1; n = 13 y Familia 2; n = 33), y secuenciación del exoma (Familia 1; n = 5 y Familia 2; n = 4) y genoma completo (Familia 2; n = 12), con el objetivo de identificar variaciones raras de nucleótido único y del número de copias que se segregaran con el fenotipo. En ambas familias, realizamos análisis de ligamiento, de asociación y estimaciones de riesgo genético. En la Familia 1, se identificaron dos arquitecturas genómicas diferentes en las dos ramas de la familia. En la primera rama, la psicosis es el resultado del efecto combinado de dos duplicaciones, DUP3p26.3 (CNTN6) y DUP16p23.3 (CDH13), y dos variantes raras de sentido falso en MACF1 y GLI2. Otras variantes raras de sentido falso identificadas también pueden estar jugando un papel importante (VPS8, TNR y GJA1). En la otra rama, la psicosis parece precipitarse debido a dos deleciones: DEL3q28 (OSTN/UTS2B) y DEL13q31.2. Varias variantes de sentido falso también pueden desempeñar un papel en esta rama (SERPINI1, CCDC141 y TNR). Además, se identificaron cuatro regiones (1q41-42.3; 3q26.2-27.3; 4q34.3-35.1 y 11q21-23.3) sugestivas de ligamiento (puntuaciones LOD > 1). El análisis de estas regiones combinado con los genes compartidos que albergan variantes raras evidenció el 6 enriquecimiento en procesos biológicos asociados a trastornos psicóticos, como la organización y el desarrollo neuronales. La arquitectura genómica de la psicosis en la Familia 2 está asociada con la región 9q31.3-q33.2, con ligamiento significativo (LODwide = 4.11, LODnarrow = 3.07). Esta región contiene cinco genes candidatos previamente asociados con trastornos mentales (ASTN2, BRINP1, C5, TLR4 y TRIM32). No se identificó ninguna variante rara compartida entre todos los individuos afectados en esta región. Contribuyendo a la arquitectura genómica de esta familia también encontramos varias variantes raras de sentido falso (CSMD1, HHAT, PALB2, SHANK2, RTN4R, TNC, CDK5RAP2, GSN, C5, KDM4C y ARHGAP19) y variantes estructurales (DUP3q29, DUP4q35.2, DUP9p24.1, DUP11p14.2, DUP18q22.1, DUP22q11.23, DEL6p21.33, DEL8p23.2 y DEL12q14.1) así como otras regiones sugestivas identificadas en el análisis de ligamiento para cada fenotipo (puntuación LOD > 1). Estas regiones están enriquecidas en genes involucrados en la sinapsis, el sistema inmunológico y el citoesqueleto. Los resultados de esta tesis confirman la heterogeneidad de la psicosis y evidencian las dificultades inherentes para entender su arquitectura genética. No obstante, también refuerzan la conveniencia de combinar diferentes aproximaciones de la genómica de sistemas para identificar variantes y genes candidatos que ayuden a entender su etiología

Disentangling the genomic architecture of psychosis in families with high prevalence through system genomic approaches

[eng] Psychotic disorders as schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders with overlapping symptomatology, high heterogeneity, and shared genetic susceptibility. Different phenotype definitions, for example, the presence of psychotic symptoms, have been proposed to reduce the phenotypic heterogeneity imposed by clinical classifications. The current consensus assumes that the genetic architecture of psychosis is the result of the combined effect of common and rare variants. Identifying rare variants associated with the disease is complicated at a population level. Therefore, analyzing families with a high prevalence of psychosis is an interesting approach to identify highly penetrant variants. In this thesis, in an attempt to disentangle the genomic architecture of psychosis, two families with high prevalence were analyzed. Two phenotypes were defined: (i) Wide, referred to any psychiatric disorder, and (ii) Narrow, referred to disorders presenting with psychosis. Family 1 of Majorcan origin had five narrow individuals. Family 2, a large family from Alpujarras, Granada (Andalucía), a region with a high prevalence of psychosis, had 42 wide subjects, 27 of which were narrow. In both Families, system genomic approaches were applied, based on karyotyping (Family 1; n = 2 and Family 2; n = 3), genotyping by SNP array (Family 1; n = 13 and Family 2; n = 33), and whole-exome (WES; Family 1; n = 5 and Family 2; n = 4) and whole-genome sequencing (WGS; Family 2; n = 12), to search for rare single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) segregating with the phenotype. In both Families, we performed genome-wide linkage analysis, family-based association analysis, and polygenic risk score estimates. In Family 1, two different genomic architectures were identified in the two family branches. In the first branch, psychosis is the result of the combined effect of two duplications DUP3p26.3 (CNTN6) and DUP16p23.3 (CDH13), and two rare missense variants in MACF1 and GLI2 genes. Other rare missense variants identified in the family may also play an important role (VPS8, TNR, and GJA1). In the other branch, psychosis seems to precipitate due to two deletions DEL3q28 (OSTN/UTS2B) and DEL13q31.2. Several missense variants may also play a role in this branch (SERPINI1, CCDC141, and TNR). Moreover, four suggestive linkage regions (LOD scores > 1) were identified in Family 1 (1q41-42.3; 3q26.2-27.3; 4q34.3-35.1 and 11q21-23.3). Comprehensive analysis of these regions combined with the shared genes harboring rare variants evidenced enrichment for biological processes associated with psychotic disorders, such as neuronal organization and development. The genomic architecture of psychosis in Family 2 is associated with the region 9q31.3-q33.2, with a significant linkage (LODwide = 4.11, LODnarrow = 3.07). This region contains five candidate genes (ASTN2, BRINP1, C5, TLR4, and TRIM32) previously associated with major mental disorders. Not a single rare variant shared among all affected individuals was identified in this region. Contributing to the genomic architecture we also found several rare missense variants (CSMD1, HHAT, PALB2, SHANK2, RTN4R, TNC, CDK5RAP2, GSN, C5, KDM4C, and ARHGAP19) and structural variants (DUP3q29, DUP4q35.2, DUP9p24.1, DUP11p14.2, DUP18q22.1, DUP22q11.23, DEL6p21.33, DEL8p23.2, and DEL12q14.1) plus other suggestive regions in both phenotype analyses (LOD score > 1). All those regions were enriched for genes involved in synapsis, the immune system, and the cytoskeleton. The results of this thesis confirm that psychosis is highly heterogeneous and evidence the inherent difficulties for understanding its genetic architecture. Nevertheless, they also strengthen the convenience of combining different system genomic approaches to identify genetic variants and potential gene candidates for understanding its genetic etiology.[cat] Els trastorns psicòtics com l’esquizofrènia i el trastorn bipolar presenten una elevada heretabilitat, simptomatologia superposada, elevada heterogeneïtat i susceptibilitat genètica compartida. S’han proposat diferent definicions fenotípiques, com per exemple, la presència de símptomes psicòtics, per reduir-ne l’heterogeneitat fenotípica. A dia d’avui hi ha un ampli consens en que l’arquitectura genètica de la psicosi és el resultat de l’efecte combinat de variants comunes i rares. La identificació de variants rares associades a la malaltia és complicada a nivell poblacional, pel que l’anàlisi de famílies amb alta prevalença és una aproximació prometedora per identificar variants d’elevada penetrància. En aquesta tesi es van analitzar dues famílies amb alta prevalença de la malaltia amb l’objectiu de comprendre millor l’arquitectura genètica de la psicosi. Es van definir dos fenotips: (i) “l’ample”, que incloïa qualsevol trastorn psiquiàtric, i (ii) el “restringit”, que incloïa trastorns que cursen amb psicosi. La família 1, d'origen mallorquí, tenia cinc individus amb fenotip “restringit”. Per contra, la família 2 de les Alpujarras (Granada), una regió amb alta prevalença de la malaltia, tenia 42 individus amb fenotip “ample”, dels quals 27 presentaven símptomes psicòtics. En ambdues famílies, es van aplicar tècniques pròpies de la genòmica de sistemes, cariotip (família 1; n = 2 i família 2; n = 3), genotipat per SNP array (família 1; n = 13 i família 2; n = 33), i seqüenciació de l’exoma (família 1; n = 5 i família 2; n = 4) i genoma complet (família 2; n = 12), amb l’objectiu de trobar variants rares, polimorfismes de nucleòtid únic i variacions en el número de còpies, que segreguessin amb el fenotip. En ambdues famílies, vam realitzar anàlisis de lligament, d’associació i estimacions de risc genètic. A la família 1, es van identificar dues arquitectures genètiques diferents en cada una de les dues branques familiars. A la primera, la psicosi és el resultat de l’efecte combinat de dues duplicacions, DUP3p26.3 (CNTN6) i DUP16p23.3 (CDH13), i de dues variants rares amb error de sentit en MACF1 i GLI2. Altres variants rares identificades també podrien estar jugant-hi un paper important (VPS8, TNR i GJA1). A l’altra branca, la psicosi sembla ser el resultat de dues delecions: DEL3q28 (OSTN/UTS2B) i DEL13q31.2. També en aquesta branca hi ha diverses variants rares que poden participar en el fenotip (SERPINI1, CCDC141 i TNR). A més, es van identificar quatre regions (1q41-42.3; 3q26.2-27.3; 4q34.3-35.1 i 11q21-23.3) suggestives de lligament (puntuacions LOD > 1). L’anàlisi d’aquestes regions i dels 4 gens portadors de variants rares va mostrar un enriquiment en processos biològics rellevants per la malaltia, com l’organització i el desenvolupament neuronal. L’arquitectura genètica de la família 2 s’associa a la regió 9q31.3-q33.2, amb un resultat de lligament significatiu (LODwide = 4.11, LODnarrow = 3.07). Aquesta regió conté cinc gens prèviament associats amb trastorns mentals (ASTN2, BRINP1, C5, TLR4 i TRIM32). No s’hi va trobar cap variant rara compartida entre tots els individus afectes. D’altres variants rares també poden estar contribuint a l’arquitectura genètica de la família incloent variants amb error de sentit (CSMD1, HHAT, PALB2, SHANK2, RTN4R, TNC, CDK5RAP2, GSN, C5, KDM4C i ARHGAP19), variants estructurals (DUP3q29, DUP4q35.2, DUP9p24.1, DUP11p14.2, DUP18q22.1, DUP22q11.23, DEL6p21.33, DEL8p23.2 i DEL12q14.1), i d’altres regions suggestives identificades en l’anàlisi de lligament d’ambdós fenotips (puntuació LOD > 1). Aquestes regions estan enriquides en gens implicats en la sinapsi, el sistema immunitari i el citoesquelet. Els resultats d’aquesta tesi confirmen d’una banda l’elevada heterogeneïtat de la psicosi i de l’altre les dificultats inherents per entendre la seva arquitectura genètica. Així mateix, també donen suport a les aproximacions basades en la genòmica de sistemes que permeten identificar variants genètiques i possibles gens candidats.[spa] Los trastornos psicóticos como la esquizofrenia y el trastorno bipolar tienen una elevada heredabilidad, sintomatología superpuesta, elevada heterogeneidad y susceptibilidad genética compartida. Se han propuesto diferentes definiciones fenotípicas, por ejemplo, la presencia de síntomas psicóticos, para reducir la heterogeneidad fenotípica. Actualmente se acepta ampliamente que la arquitectura genética de la psicosis es el resultado del efecto combinado de variantes comunes y raras. La identificación de variantes raras es complicada a nivel poblacional, por lo que el análisis de familias con alta prevalencia de psicosis es una aproximación interesante para identificar variantes penetrantes. En esta tesis, se analizaron dos familias con alta prevalencia con el objetivo de comprender la arquitectura genómica de la psicosis. Se definieron dos fenotipos: (i) “Amplio”, incluyendo cualquier trastorno psiquiátrico, y (ii) “Estrecho”, referido a los trastornos que cursan con psicosis. La familia 1 de origen mallorquín tenía cinco individuos psicóticos. La familia 2, una amplia familia de las Alpujarras (Granada), una región con una alta prevalencia de psicosis, tenía 42 individuos con fenotipo psiquiátrico, de los cuales 27 eran psicóticos. En ambas familias, se aplicaron aproximaciones de la genómica de sistemas, cariotipo (Familia 1; n = 2 y Familia 2; n = 3), genotipado por SNP array (Familia 1; n = 13 y Familia 2; n = 33), y secuenciación del exoma (Familia 1; n = 5 y Familia 2; n = 4) y genoma completo (Familia 2; n = 12), con el objetivo de identificar variaciones raras de nucleótido único y del número de copias que se segregaran con el fenotipo. En ambas familias, realizamos análisis de ligamiento, de asociación y estimaciones de riesgo genético. En la Familia 1, se identificaron dos arquitecturas genómicas diferentes en las dos ramas de la familia. En la primera rama, la psicosis es el resultado del efecto combinado de dos duplicaciones, DUP3p26.3 (CNTN6) y DUP16p23.3 (CDH13), y dos variantes raras de sentido falso en MACF1 y GLI2. Otras variantes raras de sentido falso identificadas también pueden estar jugando un papel importante (VPS8, TNR y GJA1). En la otra rama, la psicosis parece precipitarse debido a dos deleciones: DEL3q28 (OSTN/UTS2B) y DEL13q31.2. Varias variantes de sentido falso también pueden desempeñar un papel en esta rama (SERPINI1, CCDC141 y TNR). Además, se identificaron cuatro regiones (1q41-42.3; 3q26.2-27.3; 4q34.3-35.1 y 11q21-23.3) sugestivas de ligamiento (puntuaciones LOD > 1). El análisis de estas regiones combinado con los genes compartidos que albergan variantes raras evidenció el 6 enriquecimiento en procesos biológicos asociados a trastornos psicóticos, como la organización y el desarrollo neuronales. La arquitectura genómica de la psicosis en la Familia 2 está asociada con la región 9q31.3-q33.2, con ligamiento significativo (LODwide = 4.11, LODnarrow = 3.07). Esta región contiene cinco genes candidatos previamente asociados con trastornos mentales (ASTN2, BRINP1, C5, TLR4 y TRIM32). No se identificó ninguna variante rara compartida entre todos los individuos afectados en esta región. Contribuyendo a la arquitectura genómica de esta familia también encontramos varias variantes raras de sentido falso (CSMD1, HHAT, PALB2, SHANK2, RTN4R, TNC, CDK5RAP2, GSN, C5, KDM4C y ARHGAP19) y variantes estructurales (DUP3q29, DUP4q35.2, DUP9p24.1, DUP11p14.2, DUP18q22.1, DUP22q11.23, DEL6p21.33, DEL8p23.2 y DEL12q14.1) así como otras regiones sugestivas identificadas en el análisis de ligamiento para cada fenotipo (puntuación LOD > 1). Estas regiones están enriquecidas en genes involucrados en la sinapsis, el sistema inmunológico y el citoesqueleto. Los resultados de esta tesis confirman la heterogeneidad de la psicosis y evidencian las dificultades inherentes para entender su arquitectura genética. No obstante, también refuerzan la conveniencia de combinar diferentes aproximaciones de la genómica de sistemas para identificar variantes y genes candidatos que ayuden a entender su etiología

Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis

Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ -knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery

Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis

Abstract Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient’s blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4–5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery

Infective Endocarditis After Transcatheter Versus Surgical Aortic Valve Replacement

Abstract Background Scarce data are available comparing infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). This study aimed to compare the clinical presentation, microbiological profile, management, and outcomes of IE after SAVR versus TAVR. Methods Data were collected from the “Infectious Endocarditis after TAVR International” (enrollment from 2005 to 2020) and the “International Collaboration on Endocarditis” (enrollment from 2000 to 2012) registries. Only patients with an IE affecting the aortic valve prosthesis were included. A 1:1 paired matching approach was used to compare patients with TAVR and SAVR. Results A total of 1688 patients were included. Of them, 602 (35.7%) had a surgical bioprosthesis (SB), 666 (39.5%) a mechanical prosthesis, 70 (4.2%) a homograft, and 350 (20.7%) a transcatheter heart valve. In the SAVR versus TAVR matched population, the rate of new moderate or severe aortic regurgitation was higher in the SB group (43.4% vs 13.5%; P < .001), and fewer vegetations were diagnosed in the SB group (62.5% vs 82%; P < .001). Patients with an SB had a higher rate of perivalvular extension (47.9% vs 27%; P < .001) and Staphylococcus aureus was less common in this group (13.4% vs 22%; P = .033). Despite a higher rate of surgery in patients with SB (44.4% vs 27.3%; P < .001), 1-year mortality was similar (SB: 46.5%; TAVR: 44.8%; log-rank P = .697). Conclusions Clinical presentation, type of causative microorganism, and treatment differed between patients with an IE located on SB compared with TAVR. Despite these differences, both groups exhibited high and similar mortality at 1-year follow-up