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International team discovers new genes that shape brain's size, intelligence

Global collaboration identifies genes that boost or lessen risk of brain atrophy, mental illness and Alzheimer's disease

Contact: Dr. Paul Thompson (310)206-2101 thompson@loni.ucla.edu

or Elaine Schmidt, UCLA Health Sciences Media Relations (310)794-2272 eschmidt@mednet.ucla.edu

Radio Interview explaining ENIGMA (4 minutes, KCBS News 740 AM/106.9 FM, San Francisco, April 16 2012)
Radio Interview on Genes and Our 'Mental Bank Account' (7 minutes, KPCC Radio 89.3 FM, April 17 2012)

[Full article, .pdf, 1.0MB] - 104-Page Supplement for the Paper [.pdf, 2.3MB]
New York Times (April 15, 2012) - Crowd-Sourcing Expands Power of Brain Research

Bloomberg News (April 15, 2012) | Boston Globe (April 15, 2012)

Los Angeles Times (April 15, 2012) - Scientists at UCLA, worldwide collaborate to map brain size genes

TIME Magazine (April 16, 2012) - Bigger Brain and Higher IQ Linked with Specific Genetic Variants

Agence France Presse (AFP, Paris; April 15, 2012) - Tiny gene change affects brain size, IQ: scientists | France 24 (in English) | (in French) | France Soir (in French; April 15, 2012) | Yahoo Finance France (in French; April 17, 2012) | Voila.fr Actualites (in French; April 15, 2012) | My Science article (in French; by Laurence Bianchini)

Discover Magazine (April 15, 2012)

New Scientist (UK; April 16, 2012) | [Longer story in printed magazine]
Daily Telegraph (UK)

SFARI Autism Foundation (by Emily Singer) - Giant imaging study identifies genes that govern brain size |

Alzheimer's Forum (Alzforum; by Esther Landhuis) | Patexia (Commentary; by Kristin Wall) |

Yahoo News | New York Daily News | Web MD (April 16, 2012)

Medscape (April 18, 2012)

Haaretz (Israel; in Hebrew; April 15, 2012)

Agenzia Giornalistica Italia (AGI, Italy; April 15, 2012) - Gene change that affects intelligence discovered |
Le Scienze (Italy; in Italian; April 15, 2012) | La Reppublica (Italy; in Italian; April 15, 2012) | Giornalettismo (Italy; in Italian; April 15, 2012) | La Stampa (Italy; in Italian; April 17, 2012) | WellMe.it (Italy; in Italian; April 17, 2012) | Notiziario Italiano (Italy; in Italian; April 15, 2012) | Veneto Nanotech (Italy; in Italian) | Alzheimer Reise (Italy; in Italian) | Vivere Meglio Italia (Italy; in Italian; April 15, 2012)

US News and World Report/HealthDay (April 15, 2012) - Researchers ID Genes That May Determine Mental Illness

Wetenschap 24 (in Dutch; Netherlands; April 16, 2012) - with comments by ENIGMA member Dr Barbara Franke | Max Planck Institute (in English; Netherlands) | Medisch Nieuws (in Dutch; Netherlands) | Gesondheitsnet (in Dutch; Netherlands)

Medical Independent (Ireland; April 20, 2012) - with comments by ENIGMA member Dr Gary Donohoe, Trinity College Dublin, Ireland |

Waterloo Record (Canada) | Guelph Mercury (Canada) | Yahoo News Canada

Gulf Times (Qatar) | Straits Times (Singapore) | FARS News (Tehran, Iran) | The News International (Pakistan)

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Slate (in French) - HMGA2: Le gene de l'intelligence?

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El Mundo - Full Page Feature (Spain; in Spanish; April 17, 2012; Las claves geneticas de la inteligencia)

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Live Science (April 15, 2012) - Specific Genes Linked to Big Brains and Intelligence
Science Daily (April 15, 2012) - New Genes Linked to Brain Size, Intelligence
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Research Summary - by Elaine Schmidt (April 15, 2012)

In the world's largest brain imaging study to date, a team of more than 200 scientists from over 100 institutions worldwide has collaborated to map the human genes that sabotage or boost the brain's resistance to a variety of mental illnesses and Alzheimer's disease. Published April 15 in the advance online edition of Nature Genetics, the study also uncovers new genes that may explain individual differences in brain size and intelligence.

"We searched for two things in this study," said senior author Paul Thompson, professor of neurology at the David Geffen School of Medicine at UCLA and a member of the UCLA Laboratory of Neuro Imaging. "We hunted for genes that increase your risk for a single disease and can be passed onto your children. We also looked for factors that cause tissue atrophy and reduce brain size, which is a biological marker for disorders like schizophrenia, bipolar illness, depression, Alzheimer's disease and dementia."

Three years ago, Thompson's lab partnered with geneticists Nick Martin and Margaret Wright at the Queensland Institute for Medical Research in Brisbane, Australia; and with geneticist Barbara Franke of Radboud University Nijmegen Medical Centre in the Netherlands. The four investigators recruited brain-imaging labs around the world to pool their brain scans and genomic data, and the ENIGMA Project (Enhancing Neuro Imaging Genetics through Meta-Analysis) was born.

"Our individual centers couldn't review enough brain scans to obtain definitive results," said Thompson, who is also a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. "By sharing our data via the ENIGMA Project, we created a sample large enough to reveal clear patterns in genetic variation and show how these changes physically alter the brain."

In the past, neuroscientists screened the genomes of people suffering from a specific brain disease and combed their DNA to uncover a common variant. In this study, ENIGMA Project researchers measured the size of the brain and its memory centers in thousands of MRI images from 21,151 people while simultaneously screening their DNA.

"Earlier studies have uncovered risk genes for common diseases, yet it's not always understood how these genes affect the brain," explained Thompson. "This led our team to screen brain scans worldwide for genes that directly harm or protect the brain."

In poring over the data, ENIGMA Project researchers explored whether any genetic variations correlated to brain size. In particular, the scientists looked for gene variants that deplete brain tissue beyond normal in a healthy person. The sheer scale of the project allowed the team to unearth new genetic variants in people who have bigger brains as well as differences in regions critical to learning and memory.

When the scientists zeroed in on the DNA of people whose images showed smaller brains, they found a consistent relationship between subtle shifts in the genetic code and diminished memory centers. Furthermore, the same genes affected the brain in the same ways in people across diverse populations from Australia, North America and Europe, suggesting new molecular targets for drug development.

"Millions of people carry variations in their DNA that help boost or lower their brains' susceptibility to a vast range of diseases," said Thompson. "Once we identify the gene, we can design approaches to target it with a drug to reduce the risk of disease. People also can take preventive steps through exercise, diet and mental stimulation to erase the effects of a bad gene."

In an intriguing twist, ENIGMA Project investigators also discovered genes that explain individual differences in intelligence. They found that a new variant in a gene called HMGA2 affected brain size as well as a person's intelligence. DNA comprises four bases: A (adenine), C (cytosine), T (thymine) and G (guanine). People whose HMGA2 gene holds a letter "C" instead of a "T" at a specific location on the gene possessed larger brains and scored more highly on standardized IQ tests.

"This is a really exciting discovery: that a single letter change leads to a bigger brain," said Thompson. "We found fairly unequivocal proof supporting a genetic link to brain function and intelligence. For the first time, we have watertight evidence of how these genes affect the brain. This supplies us with new leads on how to mediate their impact."

Because disorders like Alzheimer's, autism and schizophrenia disrupt the brain's circuitry, the ENIGMA Project will next search for genes that influence how the brain is wired. Thompson and his colleagues will use diffusion imaging, a new type of brain scan that maps the communication pathways between cells in the living brain.

To learn more about the ENIGMA Project, go to http://enigma.loni.ucla.edu

Thompson's UCLA coauthors included first author Jason Stein, Derrek Hibar, Rudy Senstad, Neda Jahanshad, Arthur Toga, Rita Cantor, Nelson Freimer, Roel Ophoff, Kristy Hwang, Liana Apostolova and Giovanni Coppola. A total of 207 scientists worldwide are coauthors (see below for a complete list). The research received funding from hundreds of federal and private agencies around the world.

The study is freely available here.

For more information on the study, contact Paul Thompson: thompson@loni.ucla.edu

Nature Genetics Article [207 authors]:

[1] Jason L. Stein*, Sarah E. Medland*, Alejandro Arias Vasquez*, Derrek P. Hibar*, Rudy E. Senstad, Anderson M. Winkler, Roberto Toro, Katja Appel, Richard Bartecek, Orjan Bergmann, Manon Bernard, Andrew A. Brown, Dara M. Cannon, Mallar Chakravarty, Andrea Christoforou, Martin Domin, Oliver Grimm, Marisa Hollinshead, Avram J. Holmes, Georg Homuth, Jouke-Jan Hottenga, Camilla Langan, Lorna M. Lopez, Narelle K. Hansell, Kristy S. Hwang, Sungeun Kim, Gonzalo Laje, Phil H. Lee, Xinmin Liu, Eva Loth, Anbarasu Lourdusamy, Susana Munoz Maniega, Morten Mattingsdal, Sebastian Mohnke, Kwangsik Nho, Allison C. Nugent, Carol O'Brien, Martina Papmeyer, Benno Putz, Adaikalavan Ramasamy, Jerod Rasmussen, Mark Rijpkema, Shannon L. Risacher, J. Cooper Roddey, Emma J. Rose, Mina Ryten, Li Shen, Emma Sprooten, Eric Strengman, Alexander Teumer, Daniah Trabzuni, Jessica Turner, Kristel van Eijk, Theo G.M. van Erp, Marie-Jose van Tol, Katharina Wittfeld, Christiane Wolf, Saskia Woudstra, Andre Aleman, Saud Alhusaini, Laura Almasy, Elisabeth B. Binder, David G. Brohawn, Rita M. Cantor, Melanie A. Carless, Aiden Corvin, Michael Czisch, Joanne E. Curran, Gail Davies, Marcio A. A. de Almeida, Norman Delanty, Chantal Depondt, Ravi Duggirala, Thomas D. Dyer, Susanne Erk, Jesen Fagerness, Peter T. Fox, Nelson B. Freimer, Michael Gill, Harald H.H. Goering, Donald J. Hagler, David Hoehn, Florian Holsboer, Martine Hoogman, Norbert Hosten, Neda Jahanshad, Matthew P. Johnson, Dalia Kasperaviciute, Jack W. Kent, Jr., Peter Kochunov, Jack L. Lancaster, Stephen M. Lawrie, David C. Liewald, Rene Mandl, Mar Matarin, Manuel Mattheisen, Eva Meisenzahl, Ingrid Melle, Eric K. Moses, Thomas W. Muehleisen, Matthias Nauck, Markus M. Noethen, Rene L. Olvera, Massimo Pandolfo, G. Bruce Pike, Ralf Puls, Ivar Reinvang, Miguel E. Renteria, Marcella Rietschel, Joshua L. Roffman, Natalie A. Royle, Dan Rujescu, Jonathan Savitz, Hugo G. Schnack, Knut Schnell, Nina Seiferth, Colin Smith, Vidar M. Steen, Maria C. Valdes Hernandez, Martijn Van den Heuvel, Nic J. van der Wee, Neeltje E.M. Van Haren, Joris A. Veltman, Henry Volzke, Robert Walker, Lars T. Westlye, Christopher D. Whelan, Ingrid Agartz, Dorret I. Boomsma, Gianpiero L. Cavalleri, Anders M. Dale, Srdjan Djurovic, Wayne C. Drevets, Peter Hagoort, Jeremy Hall, Andreas Heinz, Clifford R. Jack, Jr., Tatiana M. Foroud, Stephanie Le Hellard, Fabio Macciardi, Grant W. Montgomery, Jean Baptiste Poline, David J. Porteous, Sanjay M. Sisodiya, John M. Starr, Jessika Sussmann, Arthur W. Toga, Dick J. Veltman, Henrik Walter, Michael W. Weiner, the Alzheimer's Disease Neuroimaging Initiative, EPIGEN Consortium, IMAGEN Consortium, Saguenay Youth Study Group, Joshua C. Bis, M. Arfan Ikram, Albert V. Smith, Vilmundur Gudnason, Christophe Tzourio, Meike W. Vernooij, Lenore J. Launer, Charles DeCarli, Sudha Seshadri, for the CHARGE Consortium, Ole A. Andreassen, Liana G. Apostolova, Mark E. Bastin, John Blangero, Han G. Brunner, Randy L. Buckner, Sven Cichon, Giovanni Coppola, Greig I. de Zubicaray, Ian J. Deary, Gary Donohoe, Eco J.C. de Geus, Thomas Espeseth, Guillen Fernandez, David C. Glahn, Hans J. Grabe, John Hardy, Hilleke E. Hulshoff Pol, Mark Jenkinson, Rene S. Kahn, Colm McDonald, Andrew M. McIntosh, Francis J. McMahon, Katie L. McMahon, Andreas Meyer-Lindenberg, Derek W. Morris, Bertram Mueller-Myhsok, Thomas E. Nichols, Roel A. Ophoff, Tomas Paus, Zdenka Pausova, Brenda W. Penninx, Steven G. Potkin, Philipp G. Saemann, Andrew J. Saykin, Gunter Schumann, Jordan W. Smoller, Joanna M. Wardlaw, Michael E. Weale, Nicholas G. Martin#, Barbara Franke#, Margaret J. Wright#, Paul M. Thompson#, for the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium. Identification of common variants associated with human hippocampal and intracranial volumes, Nature Genetics, April 15 2012. [.pdf, 1.0MB]

104-Page Supplement for the Paper, with full details [.pdf, 2.3MB]

Search the genome using ENIGMA's results to see genetic associations with brain measures [Enigma-Vis]

For those interested on the HMGA2 genetic variant's effect on height, and its partially independent effect on brain size (intracranial volume), this figure in the paper is quite useful, it's a bit buried in the paper but it's Supplementary Figure 44.

Media stories on other research projects can be found here and here.

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  • other research areas
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    Contact Information

  • Mail:

    Paul Thompson, Ph.D.
    Professor of Neurology
    UCLA Lab of Neuro-Imaging
    Dept. Neurology and Brain Research Institute
    635 Charles Young Drive, UCLA Medical Center
    Westwood, Los Angeles CA 90095-1769, USA.

  • E-mail: thompson@loni.ucla.edu
  • Tel: (310)206-2101
  • Fax: (310)206-5518