Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Oct 30;80(3):578-87.
doi: 10.1016/j.neuron.2013.10.046.

Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology

Steven A McCarroll  1 , Steven E Hyman
Affiliations
Review

Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology

Steven A McCarroll et al. Neuron. .

Abstract

Advances in genome analysis, accompanied by the assembly of large patient cohorts, are making possible successful genetic analyses of polygenic brain disorders. If the resulting molecular clues, previously hidden in the genomes of affected individuals, are to yield useful information about pathogenesis and inform the discovery of new treatments, neurobiology will have to rise to many difficult challenges. Here we review the underlying logic of the genetic investigations, describe in more detail progress in schizophrenia and autism, and outline the challenges for neurobiology that lie ahead. We argue that technologies at the disposal of neuroscience are adequately advanced to begin to study the biology of common and devastating polygenic disorders.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Different kinds of genetic variation and different approaches to genetic analysis are influenced by human population history. (a) Humans have an eccentric population history, in which small, ancestral populations rapidly expanded into a population of some seven billion individuals. (b) Genetic variants that have arisen recently in human history, including new mutations, are generally ascertained by genome sequencing. (c) Polymorphisms that were already present in the small, ancestral populations can be systematically evaluated for relationship to phenotypes, on thousands of genetic backgrounds, using inexpensive array-based assay platforms.
Figure 2
Figure 2
Emerging genetic evidence on complex brain disorders converges on specific molecular complexes. (a) Multiple subunits of voltage-gated calcium channels are among the genome's strongest associations to schizophrenia and bipolar disorder. (b) Genes encoding the postsynaptic components of excitatory synapses are implicated by both rare and common variants in schizophrenia.
See this image and copyright information in PMC

References

    1. Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, et al. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. American journal of human genetics. 2007;80:988–993. - PMC - PubMed
    1. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics. 1999;23:185–188. - PubMed
    1. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, et al. A genome-wide scan for common alleles affecting risk for autism. Human molecular genetics. 2010;19:4072–4082. - PMC - PubMed
    1. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–823. - PMC - PubMed
    1. Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009;7(5):e1000112. - PMC - PubMed

Publication types