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News Release: Mapping the Genetic Pathway for Autism

A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism [Full Text PDF]
John P Hussman , Ren-Hua Chung , Anthony J Griswold , James M Jaworkski , Daria Salyakina , Deqiong Ma , Ioanna Konidari , Patrice L Whitehead , Jeffery M Vance , Eden R Martin , Michael L Cuccaro , John R Gilbert , Jonathan L Haines and Margaret A Pericak-Vance

[Full Text HTML] Molecular Autism 2011, 2 :1  doi:10.1186/2040-2392-2-1
[Additional Files including candidate genes and supporting literature]
Published: 19 January 2011

Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism.

GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology.

Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets.

As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism.



The following papers are part of an ongoing research partnership with Dr. Margaret Pericak-Vance and Dr. Jeffery Vance, now of the Hussman Institute of Human Genomics at the University of Miami, to identify genetic factors involved in autism:

A genome-wide association study of autism reveals a common novel risk locus at 5p14.1.
Ma D, Salyakina D, Jaworski JM, Konidari I, Whitehead PL, Andersen AN, Hoffman JD, Slifer SH, Hedges DJ, Cukier HN, Griswold AJ, McCauley JL, Beecham GW, Wright HH, Abramson RK, Martin ER, Hussman JP, Gilbert JR, Cuccaro ML, Haines JL, Pericak-Vance MA. Ann Hum Genet . 2009 May;73(Pt 3):263-73.

Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.
Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, Delong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA.  American Journal of Human Genetics. 2005 Sep;77(3):377-88

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.
Ashley-Koch AE, Mei H, Jaworski J, Ma DQ, Ritchie MD, Menold MM, Delong GR, Abramson RK, Wright HH, Hussman JP, Cuccaro ML, Gilbert JR, Martin ER, Pericak-Vance MA. Ann Hum Genet. 2006 May;70(Pt 3):281-92.

Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.
Collins AL, Ma DQ, Whitehead PL, Martin ER, Wright HH, Abramson RK, Hussman JP, Haines JL, Cuccaro ML, Gilbert JR, Pericak-Vance MA. Neurogenetics. 2006 Jul;7(3):167-74. Epub 2006 Jun 13

Other research supported by the Hussman Foundation:

Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications.
Yip J, Soghomonian JJ, Blatt GJ. Acta Neuropathol (Berl). 2007 Jan 18; Epub.

Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism (PDF)
John P. Hussman, Ph.D., Journal of Autism & Developmental Disorders, April 2001

Further research in support of the hypothesis linking autism and suppressed GABAergic inhibitory tone:

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders.
Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM. Hum Mol Genet. 2007 Mar 5; Epub.

An inversion inv(4)(p12-p15.3) in autistic siblings implicates the 4p GABA receptor gene cluster.
Vincent JB, Horike SI, Choufani S, Paterson AD, Roberts W, Szatmari P, Weksberg R, Fernandex B, Scherer SW. Journal of Med. Genet., 2006 May;43(5):429-34. Epub 2006 Mar 23.

A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.
McCauley JL, Olson LM, Delahanty R, Amin T, Nurmi EL, Organ EL, Jacobs MM, Folstein SE, Haines JL, Sutcliffe JS. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131(1):51-9.

Disruption in the inhibitory architecture of the cell minicolumn: implications for autism

Casanova MF, Buxhoeveden D, Gomez J., Neuroscientist. 2003 Dec;9(6):496-507.

Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13
Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS. J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):856-63.

Association between a GABRB3 polymorphism and autism.
Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R., Mol Psychiatry. 2002;7(3):311-6.

Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study.
Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML., J Autism Dev Disord. 2001 Dec;31(6):537-43.

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