Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa.
Since identification of the genetic component in anorexia nervosa (AN), genes that partake in serotonergic and dopaminergic systems and in hormonal and weight regulation have been suggested as potential candidates for AN susceptibility. We propose another set of candidate genes. Those are genes that are involved in the signaling pathway using NMDA-R and SK channels and have been suggested as possible effectors of NMDA-R driven signaling. The role of NMDA-R in the etiology of schizophrenia has already been substantiated on various levels. Several studies based on population and family groups have implicated SK3 in schizophrenia and more recently in AN as well. Our study group consisted of 90 AN family trios. We examined the transmission of two potentially functional polymorphisms, 5073T>G polymorphism in the gene encoding the NR2B subunit of NMDA-R and CAG repeats in the coding region of SK3 channel gene. Using HHRR and TDT approaches, we found that both polymorphisms were preferentially transmitted to AN offspring (TDT yielded chi(2)=5.01, p=0.025 for NR2B 5073G alleles and chi(2)=11.75, p<0.001 for SK3 L alleles including >19 repeats). Distribution analysis of the combined NR2B/SK3 genotypes suggests that the contribution of both polymorphisms to AN risk is independent and cumulative (OR=2.44 for NR2B GG genotype and OR=3.01 for SK3 SL and LL genotypes, and OR=6.8 for the combined NR2B/SK3 genotypes including high-risk alleles). These findings point to the contribution of genes associated with the NMDA-R signaling pathway to predisposition and development of AN.
Koronyo-Hamaoui
Maya
M
The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer 52621, Israel.
Frisch
Amos
A
Stein
Daniel
D
Denziger
Yardena
Y
Leor
Shani
S
Michaelovsky
Elena
E
Laufer
Neil
N
Carel
Cynthia
C
Fennig
Silvana
S
Mimouni
Mark
M
Ram
Anca
A
Zubery
Eynat
E
Jeczmien
Pablo
P
Apter
Alan
A
Weizman
Abraham
A
Gak
Eva
E
D000293:Adolescent; D000483:Alleles; D000856:Anorexia Nervosa / Q000175:diagnosis / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics
D017931:DNA Primers; C406328:KCNN3 protein, human; C485096:NR2B protein (1292-1308); D010446:Peptide Fragments; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels