TY - JOUR
T1 - Analysis of the autism chromosome 2 linkage region
T2 - GAD1 and other candidate genes
AU - Rabionet, Raquel
AU - Jaworski, James M.
AU - Ashley-Koch, Allison E.
AU - Martin, Eden R.
AU - Sutcliffe, James S.
AU - Haines, Jonathan L.
AU - DeLong, G. Robert
AU - Abramson, Ruth K.
AU - Wright, Harry H.
AU - Cuccaro, Michael L.
AU - Gilbert, John R.
AU - Pericak-Vance, Margaret A.
N1 - Funding Information:
We wish to thank the patients with autism and family members who agreed to participate in this study and the personnel of the Center for Human Genetics at Duke University Medical Center, for their input on this project. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. Special thanks to Dr. Susan Folstein for her valuable contribution. This research was supported in part by National Institutes of Health (NIH) program project grant NS26630, NIH R01 grant NS36768, and by the National Alliance of Autism Research (NAAR). The research conducted in this study complies with current U.S. laws.
PY - 2004/12/6
Y1 - 2004/12/6
N2 - Autism has a strong and complex genetic component, involving several genes. Genomic screens, including our own, have shown suggestive evidence for linkage over a 20-30 cM region on chromosome 2q31-q33. Two subsequent reports showed that the linkage evidence increased in the subset of families with phrase speech delay (PSD), defined as onset of phrase speech later than 3 years of age. To further investigate the linkage in the presumptive candidate region, microsatellite markers in a 2 cM grid covering the interval from 164 to 203 cM were analyzed in 110 multiplex (2 or more sampled autism patients) families. A maximum heterogeneity LOD (HLOD) score of 1.54 was detected at D2S1776 (173 cM) in the overall dataset (dominant model), increasing to 1.71 in the PSD subset. While not conclusive, these data continue to provide suggestive evidence for linkage, particularly considering replication by multiple independent groups. Positive LOD scores extended over the entire region, continuing to define a broad candidate interval. Association studies were performed on several functional candidates mapping within the region. These included GAD1, encoding GAD67, whose levels are reduced in autopsy brain material from autistic subjects, and STK17B, ABI2, CTLA4, CD28, NEUROD1, PDE1A, HOXD1 and DLX2. We found no evidence for significant allelic association between autism and any of these candidates, suggesting that they do not play a major role in the genetics of autism or that substantial allelic heterogeneity at any one of these loci dilutes potential disease-allele association.
AB - Autism has a strong and complex genetic component, involving several genes. Genomic screens, including our own, have shown suggestive evidence for linkage over a 20-30 cM region on chromosome 2q31-q33. Two subsequent reports showed that the linkage evidence increased in the subset of families with phrase speech delay (PSD), defined as onset of phrase speech later than 3 years of age. To further investigate the linkage in the presumptive candidate region, microsatellite markers in a 2 cM grid covering the interval from 164 to 203 cM were analyzed in 110 multiplex (2 or more sampled autism patients) families. A maximum heterogeneity LOD (HLOD) score of 1.54 was detected at D2S1776 (173 cM) in the overall dataset (dominant model), increasing to 1.71 in the PSD subset. While not conclusive, these data continue to provide suggestive evidence for linkage, particularly considering replication by multiple independent groups. Positive LOD scores extended over the entire region, continuing to define a broad candidate interval. Association studies were performed on several functional candidates mapping within the region. These included GAD1, encoding GAD67, whose levels are reduced in autopsy brain material from autistic subjects, and STK17B, ABI2, CTLA4, CD28, NEUROD1, PDE1A, HOXD1 and DLX2. We found no evidence for significant allelic association between autism and any of these candidates, suggesting that they do not play a major role in the genetics of autism or that substantial allelic heterogeneity at any one of these loci dilutes potential disease-allele association.
KW - Association
KW - Autism
KW - Candidate genes
KW - GAD1
UR - http://www.scopus.com/inward/record.url?scp=7944233488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=7944233488&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2004.09.037
DO - 10.1016/j.neulet.2004.09.037
M3 - Article
C2 - 15542242
AN - SCOPUS:7944233488
VL - 372
SP - 209
EP - 214
JO - Neuroscience Letters
JF - Neuroscience Letters
SN - 0304-3940
IS - 3
ER -