Dectin-1 Polymorphism: A Genetic Disease Specifier in Autism Spectrum Disorders?
BACKGROUND
In autism spectrum disorders (ASD), complex gene-environment interactions contribute to disease onset and progress. Given that gastro-intestinal dysfunctions are common in ASD, we postulated involvement of microbial dysbiosis in ASD and investigated, under a case-control design, the influence of DNA polymorphisms in the CLEC7A gene that encodes a pivotal fungal sensor, Dectin-1.


METHODS
DNAs from 478 ASD patients and 351 healthy controls (HC) were analyzed for the CLEC7A rs16910631G/A and rs2078178 A/G single nucleotide polymorphisms (SNPs). Differences in the distribution of allele, genotype and haplotype by Chi-square testing and nonparametric analysis by Kruskal-Wallis/Mann-Whitney tests, where appropriate, were performed. The free statistical package R.2.13 software was used for the statistical analysis.


RESULTS
We found that the CLEC7A rs2078178 G allele and GG genotype were more prevalent in HC as compared to ASD but failed to reach statistical significance for the latter (pc = 0.01, 0.06 respectively). However, after phenotype-based stratification, the CLEC7A rs2078178 G allele and GG genotype were found to be significantly more frequent in the Asperger group as compared to other ASD subsets (pc = 0.02, 0.01), a finding reinforced by haplotype analysis (rs2078178/rs16910631 G-G/G-G) (pc = 0.002). Further, intellectual quotient (IQ)-based stratification of ASD patients revealed that IQ values increase linearly along the CLEC7A rs2078178 AA, AG and GG genotypes (p = 0.05) and in a recessive manner (GG vs. AA+AG p = 0.02), further confirmed by haplotype distribution (CLEC7A rs2078178-16910631; A-G/A-G, A-G/G-G and G-G/G-G, p = 0.02, G-G/G-G vs. others, p = 0.01).


CONCLUSIONS
Our data suggest that the genetic diversity of CLEC7A gene influences the ASD phenotype by behaving as a disease specifier and imply that the genetic control of innate immune response could determine the ASD phenotype.
INSERM, U1160, Hôpital Saint Louis, Paris, France; INSERM, U955, Psychiatrie Génétique, Créteil, France; Fondation FondaMental, Créteil, France.
Meriem
M
Bennabi
DHU Protect, Service de Psychiatrie de l'Enfant et de l'Adolescent, Hôpital Robert Debré, Paris, France; Département de Génétique Humaine et Fonctions Cognitives, Institut Pasteur, Paris, France.
Richard
R
Delorme
INSERM, U1160, Hôpital Saint Louis, Paris, France; INSERM, U955, Psychiatrie Génétique, Créteil, France; Fondation FondaMental, Créteil, France.
José
J
Oliveira
Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France.
Catherine
C
Fortier
INSERM, U955, Psychiatrie Génétique, Créteil, France; Fondation FondaMental, Créteil, France.
Mohamed
M
Lajnef
INSERM, U1160, Hôpital Saint Louis, Paris, France.
Wahid
W
Boukouaci
INSERM, U1137, Hôpital Bichat, Paris, France; Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.
Jean-Paul
JP
Feugeas
Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France.
François
F
Marzais
INSERM, U955, Psychiatrie Génétique, Créteil, France; Fondation FondaMental, Créteil, France.
Alexandru
A
Gaman
Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France; Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.
Dominique
D
Charron
Centre de Ressources Biologiques, Hôpitaux Universitaires Henri Mondor, Créteil, France.
Bijan
B
Ghaleh
INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France.
Rajagopal
R
Krishnamoorthy
INSERM, U955, Psychiatrie Génétique, Créteil, France; Fondation FondaMental, Créteil, France; AP-HP, Pôle de Psychiatrie, DHU PePSY, Hôpitaux Universitaires Henri Mondor, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France.
Marion
M
Leboyer
INSERM, U1160, Hôpital Saint Louis, Paris, France; Fondation FondaMental, Créteil, France; Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France; Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.
Ryad
R
Tamouza
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000067877:Autism Spectrum Disorder / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D064806:Dysbiosis / Q000150:complications / Q000235:genetics* / Q000382:microbiology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000099181:Dectin-1
D037181:Lectins, C-Type; C546929:CLEC7A protein, human; D000099181:Dectin-1