Confirmation that a specific haplotype of the dopamine transporter gene is associated with combined type ADHD.
Introduction: One of the most prominent findings in genetics research on ADHD is the association with the 10-repeat-allele of a variable number tandem repeat (VNTR) in the 3'-untranslated region of the DA transporter gene. -- Despite a large number of positive reports the net-effect across studies is small with evidence for heterogeneity. -- One source of heterogeneity could arise if the 10-repeat allele tags a nearby functional variant (in partial linkage disequilibrium (LD) with the 10-repeat allele, with different levels of LD occurring in different populations) or interacts with another locus (additional DNA variants in DAT1 gene). Brookes et al., 2006 Arch. Gen. Psychiat., 63, 74-81 reported the association of ADHD with a sub-group of chromosomes, containing the 10-repeat-allele & the 3-repeat-allele of another VNTR in intron 8 a) The IMAGE final sample -- consisted of 998 families with 1,159 DSM-IV combined type probands. DNA from both parents available for 83.9% of cases, & 1 parent for 16.1% of cases. 93.5% were Ms, 61.5% had co-morbid oppositional defiant disorder & 23.2% conduct disorder. 76% of the sample was receiving medication for ADHD at the time of the research evaluations. Analysis was performed using the transmission disequilibrium test implemented in UNPHASED (www.hgmp.mrc.ac.uk/Registered/Options/unphased.html). b) We now report further replication of this finding (above)-- . with an overall odds ratio of 1.4 across our samples (P = 4.26 x 10-5, and haplotype-specific-P =6 x 10-7). (i.e., combination of 10-repeat allele with 3-repeat allele of a 30-bp VNTR located within intron 8 -- all other haplotype combinations are under-transmitted). c) These data-challenge -- meta-analyses suggesting there is no or little effect of DAT1 variation on risk for ADHD. Further investigation of functional variation across DAT1 is required.
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