Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3

Abstract

Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. To fine map this locus we carried out tests of allelic association using 30 genetic markers near the telomere at 21q22.3 in 600 bipolar research subjects and 450 ancestrally matched supernormal control subjects. We found significant allelic association with the microsatellite markers D21S171 (P ¼ 0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P ¼ 0.008) and rs1785467 (P ¼ 0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P ¼ 0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P ¼ 0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P ¼ 0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder.

TRP Channels

“…These include cardiovascular diseases, sensory deficits, abnormal sensitivities to pain, gastrointestinal diseases, additional renal and neurodegenerative diseases, certain cancers, asthma, and even psychiatric diseases. Consistent with this last possibility is the association of alterations in TRPM2 with bipolar disorder (236,237). Finally, TRP channels are exciting targets for drug development.…”

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

“…Studies using TRPM2(Ϫ/Ϫ) mice suggest that the channel controls reactive oxygen speciesinduced chemokine production in monocytes and neutrophil infiltration in a mouse model of inflammation (Yamamoto et al, 2008). Human genetics studies indicate the potential involvement of TRPM2 in bipolar disorders (McQuillin et al, 2006). In addition, an inactivating proline-to-leucine substitution at position 1018 in TRPM2 is found in two related neurodegenerative disorders, amyotrophic lateral sclerosis and Parkinsonism/dementia complex, that have a high incidence on the Pacific Islands of Guam and Rota (Hermosura et al, 2008).…”

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications

“…A single-nucleotide polymorphism of the TRPM2 gene, which encodes for a calcium channel receptor, has been strongly associated with bipolar disorder and is understood to cause cellular calcium dysregulation in response to oxidative stress (McQuillin et al, 2006). Dysregulation of secondmessenger calcium has been described in bipolar disorder, and the modulation of this is thought to be a therapeutic mediating mechanism of lithium (Berk et al, 1995(Berk et al, , 1996.…”