MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India.
BACKGROUND
Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India.


METHODS
All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders.


RESULTS
We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in approximately 6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD.


CONCLUSIONS
Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder.
Functional Genomics Unit, Institute of Genomics and Integrative Biology (CSIR), Delhi, India.
Ranjana
R
Verma
Mitali
M
Mukerji
Deepak
D
Grover
Chandrika
C
B-Rao
Swapan Kumar
SK
Das
Shobana
S
Kubendran
Sanjeev
S
Jain
Samir K
SK
Brahmachari
D000328:Adult; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007194:India / Q000453:epidemiology; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D012560:Schizophrenia, Catatonic / Q000235:genetics
C425069:MLC1 protein, human; D008565:Membrane Proteins