A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
John P, Hussman Institute for Human Genomics, University of Miami, 1501 NW 10th Avenue, Miami, FL 33136, USA. mpericak@med.miami.edu.
John P
JP
Hussman
Ren-Hua
RH
Chung
Anthony J
AJ
Griswold
James M
JM
Jaworski
Daria
D
Salyakina
Deqiong
D
Ma
Ioanna
I
Konidari
Patrice L
PL
Whitehead
Jeffery M
JM
Vance
Eden R
ER
Martin
Michael L
ML
Cuccaro
John R
JR
Gilbert
Jonathan L
JL
Haines
Margaret A
MA
Pericak-Vance
Exp Cell Res. 2006 Jul 15;312(12):2379-93
16730001
Mol Psychiatry. 2003 Nov;8(11):916-24
14593429
J Child Psychol Psychiatry. 1989 May;30(3):405-16
2745591
Mol Cell Biol. 2008 Jul;28(14):4494-506
18474614
J Neurochem. 2007 Jul;102(2):324-32
17596209
Psychol Med. 1995 Jan;25(1):63-77
7792363
Neurogenetics. 2006 Jul;7(3):167-74
16770606
Neuron. 1998 Nov;21(5):1093-100
9856464
Am J Med Genet. 2001 Aug 8;105(6):521-4
11496368
Ann Hum Genet. 2009 May;73(Pt 3):263-73
19456320
Front Biosci (Landmark Ed). 2010 Jan 01;15(2):626-44
20036837
Genetics. 2002 Dec;162(4):1687-702
12524342
Am J Hum Genet. 2005 Jun;76(6):950-66
15830322
Diabetes. 2009 Jan;58(1):290-5
18840781
J Med Genet. 2003 Nov;40(11):e119
14627686
Mol Cell Biol. 2009 Dec;29(23):6321-34
19805522
Nat Protoc. 2009;4(1):44-57
19131956
J Neurosci. 2009 Apr 29;29(17):5546-57
19403822
Genet Epidemiol. 2007 Sep;31(6):577-93
17443704
ASN Neuro. 2010 Mar 31;2(2):e00031
20360946
Neurology. 2002 Feb 12;58(3):428-32
11839843
Neurosci Lett. 2007 Nov 20;428(1):1-6
17950529
Int J Dev Neurosci. 2005 Apr-May;23(2-3):183-7
15749244
J Biol Chem. 2006 Jun 16;281(24):16189-92
16497667
Am J Hum Genet. 1999 Feb;64(2):641-9
9973303
Science. 2002 Jun 21;296(5576):2225-9
12029063
Curr Opin Neurol. 2010 Apr;23(2):124-30
20154614
Hum Mol Genet. 2010 Mar 1;19(5):953-62
20007504
Biol Cell. 2002 Oct;94(6):327-34
12500940
J Pediatr Psychol. 1985 Jun;10(2):215-25
4020603
Mol Cell Neurosci. 2010 Jan;43(1):81-9
19800004
Cereb Cortex. 2000 Oct;10(10):981-91
11007549
Philos Trans R Soc Lond B Biol Sci. 2009 May 27;364(1522):1433-6
19528027
Nat Genet. 2000 May;25(1):25-9
10802651
Genome Biol. 2003;4(5):P3
12734009
Mol Cell Biol. 2008 Dec;28(23):7109-25
18824540
Am J Hum Genet. 2006 Feb;78(2):231-42
16365833
Cereb Cortex. 2000 Oct;10(10):992-1004
11007550
Am J Hum Genet. 2008 Feb;82(2):477-88
18252227
Stat Sci. 2009 Nov;24(4):398-413
20711421
Hum Hered. 2002;53(2):79-91
12037407
J Cell Biol. 2000 Aug 7;150(3):567-80
10931868
Biophys J. 2007 Feb 1;92(3):744-68
17098793
Nature. 2009 Oct 8;461(7265):802-8
19812673
J Neurosci. 2005 Aug 17;25(33):7669-81
16107653
Nature. 2003 Jun 26;423(6943):990-5
12827203
Acta Neuropathol. 2010 Jun;119(6):755-70
20198484
Nat Cell Biol. 2005 Aug;7(8):797-807
16025104
Nat Neurosci. 2004 Sep;7(9):923-9
15286792
Epidemiology. 2008 Sep;19(5):649-51; discussion 657-8
18703928
Nature. 2010 Jul 15;466(7304):368-72
20531469
Hum Mol Genet. 2009 Apr 15;18(8):1415-23
19174478
Eur J Hum Genet. 2001 Apr;9(4):291-300
11313774
Hippocampus. 2008;18(4):349-63
18064706
Science. 1997 Feb 28;275(5304):1328-9; author reply 1329-30
9064791
Neuron. 1994 Sep;13(3):583-94
7917292
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3222-7
20133610
Cell Signal. 2008 Jun;20(6):1061-72
18302981
Genet Epidemiol. 2002 Feb;22(2):170-85
11788962
J Child Psychol Psychiatry. 1994 Jul;35(5):877-900
7962246
Sci Signal. 2009 Jul 14;2(79):ra34
19602704
PLoS Genet. 2006 Dec;2(12):e190
17194218
Nature. 2009 May 28;459(7246):528-33
19404256
Genet Epidemiol. 2007 Jan;31(1):9-17
17086514
Eur J Neurosci. 2009 Oct;30(7):1193-208
19788569
Hum Hered. 2006;61(4):189-99
16877866
Exp Cell Res. 2008 Aug 15;314(14):2603-17
18586028
Genes Dev. 2005 Jan 1;19(1):1-49
15630019
J Neurosci Methods. 2008 Feb 15;168(1):195-202
17963844
Acta Neuropathol. 1996;91(1):117-9
8773156
Nat Rev Genet. 2008 May;9(5):356-69
18398418
Am J Hum Genet. 2002 May;70(5):1257-68
11923914
Nat Genet. 2003 May;34(1):27-9
12669065
Mol Psychiatry. 2004 May;9(5):474-84
15024396
Trends Neurosci. 2006 Jul;29(7):349-358
16808981
Physiology (Bethesda). 2006 Feb;21:38-47
16443821
Mol Cell Neurosci. 1996 Aug;8(2/3):99-111
8954625
Nat Rev Genet. 2001 Dec;2(12):943-55
11733747
Nat Genet. 2007 Jan;39(1):25-7
17173049
Am J Hum Genet. 2003 Apr;72(4):850-68
12647259