Alternative transcripts and evidence of imprinting of GNAL on 18p11.2

Abstract

Genetic studies implicating the region of human chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. We have identified a transcriptional variant of the GNAL gene in this region, employing an alternative first exon that is 5 0 to the originally identified start site. This alternative GNAL transcript encodes a longer functional variant of the stimulatory Gprotein alpha subunit, G olf . The isoforms of G olf display different expression patterns in the CNS and functionally couple to the dopamine D1 receptor when heterologously expressed in Sf9 cells. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated, a hallmark of genomic imprinting. These results suggest that GNAL, and possibly other genes in the region, is subject to epigenetic regulation and strengthen the case for a susceptibility gene in this region.

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

“…To our knowledge, this is the first time that GNAL was investigated in relation to ADHD. Our findings of biased transmission of maternal, but not paternal, alleles of rs2161961 and rs8098539, are consistent with the presence of parental effect and with genomic imprinting of the GNAL gene region (Corradi et al, 2005).…”

“…Furthermore, molecular studies assessing methylation status of the two promoters of the gene suggest that GNAL is subject to epigenetic regulation (Corradi et al, 2005). We thus examined the data for the presence of a parent-of-origin effect (Table 4).…”

“…Exons are indicated by boxes and markers are shown above the gene. Two major alternative transcription start sites have been described for GNAL, giving rise to isoforms that differ in their first exons (1A or 1B), but share exons 2 to 12 (Corradi et al, 2005;Vuoristo et al, 2000). Table 1 Pairwise linkage disequilibrium relationships (D′ and Δ 2 ) a between the GNAL markers b,c Quantitative analysis of GNAL allele transmission in relation to ADHD symptom scores reported by parents (PICS-IV) and teacher (TTI-IV) Table 4 TDT analysis of GNAL polymorphisms by the sex of the transmitting parent …”

“…We tested for the non-random transmission of alleles of 12 single nucleotide polymorphisms (SNPs) using the transmission/ disequilibrium test (TDT) statistic (Spielman and Ewens, 1996). Given previous findings suggesting parent-of-origin effects at 18p and evidence of epigenetic modification of GNAL (Corradi et al, 2005), we also assessed transmissions from mothers and fathers separately. Finally, we performed quantitative analysis using ADHD inattentive and hyperactive/ impulsive symptom counts.…”

Dense SNP association study for bipolar I disorder on chromosome 18p11 suggests two loci with excess paternal transmission

“…However, a recent study finds evidence of parent-of-origindependent expression for an alternative transcript of GNAL, which encodes G olf , the alpha subunit of a heretotrimeric stimulatory G-protein that may functionally associate with the dopamine D1 receptor. 51 GNAL has previously been investigated for parent-oforigin effects in bipolar disorder, and no association has been reported; however, this study tested a single marker in a small number of trios. 13 GNAL maps more than 10 Mb distal to the loci reported in this study.…”