Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers
Daniel E. Vosberg,Yu Zhang,Aurore Menegaux,Aurore Menegaux,Amanda Chalupa,Colleen Manitt,Simone P. Zehntner,Conrad Eng,Kristina DeDuck,Dominique Allard,Alain Dagher,Chawki Benkelfat,Myriam Srour,Ridha Joober,Ridha Joober,Franco Lepore,Guy A. Rouleau,Hugo Théoret,Barry J. Bedell,Cecilia Flores,Marco Leyton +20 more
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Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.Abstract:
The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC+/- mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/- mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.read more
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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Phil Lee,Verneri Anttila,Hyejung Won,Yen-Chen Anne Feng,Jacob Rosenthal,Zhaozhong Zhu,Elliot M. Tucker-Drob,Michel G. Nivard,Andrew D. Grotzinger,Danielle Posthuma,Meg M.-J. Wang,Dongmei Yu,Eli A. Stahl,Raymond K. Walters,Richard Anney,Laramie E. Duncan,Tian Ge,Rolf Adolfsson,Tobias Banaschewski,Sintia Iole Belangero,Edwin H. Cook,Giovanni Coppola,Eske M. Derks,Pieter J. Hoekstra,Jaakko Kaprio,Anna Keski-Rahkonen,George Kirov,George Kirov,Henry R. Kranzler,Jurjen J. Luykx,Luis Augusto Rohde,Clement C. Zai,Esben Agerbo,Maria Arranz,Philip Asherson,Marie Bækvad-Hansen,Gisli Baldursson,Mark A. Bellgrove,Richard A. Belliveau,Jan K. Buitelaar,Christie L. Burton,Jonas Bybjerg-Grauholm,Miquel Casas,Felecia Cerrato,Kimberly Chambert,Claire Churchhouse,Bru Cormand,Jennifer Crosbie,Søren Dalsgaard,Ditte Demontis,Alysa E. Doyle,Ashley Dumont,Josephine Elia,Jakob Grove,Olafur O Gudmundsson,Jan Haavik,Hakon Hakonarson,Christine Søholm Hansen,Catharina A. Hartman,Ziarih Hawi,Amaia Hervás,David M. Hougaard,Daniel P. Howrigan,Hailiang Huang,Jonna Kuntsi,Kate Langley,Klaus-Peter Lesch,Patrick W. L. Leung,Sandra K. Loo,Joanna Martin,Alicia R. Martin,James J. McGough,Sarah E. Medland,Jennifer L. Moran,Ole Mors,Preben Bo Mortensen,Robert D. Oades,Duncan S. Palmer,Carsten Bøcker Pedersen,Marianne Giørtz Pedersen,Triinu Peters,Timothy Poterba,Jesper Buchhave Poulsen,Josep Antoni Ramos-Quiroga,Andreas Reif,Marta Ribasés,Aribert Rothenberger,Paula Rovira,Cristina Sánchez-Mora,F. Kyle Satterstrom,Russell Schachar,María Soler Artigas,Stacy Steinberg,Hreinn Stefansson,Patrick Turley,G. Bragi Walters,Thomas Werge,Tetyana Zayats,Dan E. Arking,Francesco Bettella,Joseph D. Buxbaum,Jane H. Christensen,Ryan L. Collins,Hilary Coon,Silvia De Rubeis,Richard Delorme,Dorothy E. Grice,Thomas Hansen,Peter Holmans,Sigrun Hope,Christina M. 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TL;DR: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes.
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Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders
Phil Lee,Anttila,Hyejung Won,Yen-Chen Anne Feng,Jacob Rosenthal,Zhaozhong Zhu,Elliot M. Tucker-Drob,Michel G. Nivard,Andrew D. Grotzinger,Danielle Posthuma,Wang Mm,Dongmei Yu,E Stahl,Raymond K. Walters,Richard Anney,Laramie E. Duncan,Sintia Iole Belangero,Jurjen J. Luykx,Henry R. Kranzler,Anna Keski-Rahkonen,Edwin H. Cook,G. Kirov,Giovanni Coppola,J Kaprio,Clement C. Zai,Pieter J. Hoekstra,Tobias Banaschewski,Luis Augusto Rohde,Patrick F. Sullivan,Barbara Franke,Daly Mj,Cynthia M. Bulik,Lewis Cm,McIntosh Am,Michael Conlon O'Donovan,Amanda B Zheutlin,Andreassen Oa,Borglum Ad,Breen G,Howard J. Edenberg,Fanous Ah,Faraone Sv,Gelernter J,Carol A. Mathews,Mattheisen M,Karen S. Mitchell,Michael C. Neale,John I. Nurnberger,Ripke S,Santangelo Sl,Jeremiah M. Scharf,Stein Mb,Thornton Lm,Walters Jt,Wray Nr,Geschwind Dh,Benjamin M. Neale,Kenneth S. Kendler,Smoller Jw +58 more
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The Netrin-1/DCC guidance cue pathway as a molecular target in depression: Translational evidence
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