Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis.
BACKGROUND
Autism is a complex, heterogeneous, behaviorally-defined disorder characterized by disruptions of the nervous system and of other systems such as the pituitary-hypothalamic axis. In a previous genome wide screen, we reported linkage of autism with a 1.2 Megabase interval on chromosome 5q31. For the current study, we hypothesized that 3 of the genes in this region could be involved in the development of autism: 1) paired-like homeodomain transcription factor 1 (PITX1), which is a key regulator of hormones within the pituitary-hypothalamic axis, 2) neurogenin 1, a transcription factor involved in neurogenesis, and 3) histone family member Y (H2AFY), which is involved in X-chromosome inactivation in females and could explain the 4:1 male:female gender distortion present in autism.


METHODS
A total of 276 families from the Autism Genetic Resource Exchange (AGRE) repository composed of 1086 individuals including 530 affected children were included in the study. Single nucleotide polymorphisms tagging the three candidate genes were genotyped on the initial linkage sample of 116 families. A second step of analysis was performed using tightly linked SNPs covering the PITX1 gene. Association was evaluated using the FBAT software version 1.7.3 for single SNP analysis and the HBAT command from the same package for haplotype analysis respectively.


RESULTS
Association between SNPs and autism was only detected for PITX1. Haplotype analysis within PITX1 showed evidence for overtransmission of the A-C haplotype of markers rs11959298 - rs6596189 (p = 0.0004). Individuals homozygous or heterozygous for the A-C haplotype risk allele were 2.54 and 1.59 fold more likely to be autistic than individuals who were not carrying the allele, respectively.


CONCLUSIONS
Strong and consistent association was observed between a 2 SNPs within PITX1 and autism. Our data suggest that PITX1, a key regulator of hormones within the pituitary-hypothalamic axis, may be implicated in the etiology of autism.
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Anne
A
Philippi
Frédéric
F
Tores
Jérome
J
Carayol
Francis
F
Rousseau
Mélanie
M
Letexier
Elke
E
Roschmann
Pierre
P
Lindenbaum
Abdel
A
Benajjou
Karine
K
Fontaine
Céline
C
Vazart
Philippe
P
Gesnouin
Peter
P
Brooks
Jörg
J
Hager
D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005801:Genes, Homeobox / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017678:Sex Distribution; D035781:Siblings
D051792:Basic Helix-Loop-Helix Proteins; D005819:Genetic Markers; D006657:Histones; D009419:Nerve Tissue Proteins; D051761:Paired Box Transcription Factors; C430886:MACROH2A2 protein, human; C105389:NEUROG1 protein, human; C101485:homeobox protein PITX1