Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18.
BACKGROUND
Febrile seizures (FSs) are the most common form of childhood seizures, and genetic factors play a role in susceptibility to FS.


OBJECTIVE
To identify novel loci and genes associated with susceptibility to FS.


METHODS
Study participants were the FS probands and family members of 59 Japanese nuclear families (223 members including 112 affected children). Forty-eight of these families had at least two affected children for which genome-wide linkage screening was carried out. The Genehunter software was used to perform nonparametric multipoint linkage analysis. Mutational and association analyses were conducted in all 59 Japanese FS families.


RESULTS
Genotyping data of 407 microsatellite markers suggested linkage of FSs to chromosome 18p11.2 (non-parametric linkage score = 3.68, p = 0.0001). This region includes the IMPA2 gene, which encodes myo-inositol monophosphatase (IMPase) 2. In the phosphatidylinositol-signaling pathway, IMPase is inhibited by lithium, which has a proconvulsant effect, and is stimulated by carbamazepine, an anticonvulsant. A systematic search was performed for mutations in IMPA2 in 24 unrelated randomly selected Japanese FS patients; seven variants were detected. Haplotype analysis revealed an association of a common haplotype in IMPA2 with FSs (p = 0.0009).


CONCLUSIONS
The authors found a novel locus on chromosome 18p11.2 for febrile seizures (FSs). IMPA2 is likely to be an FS susceptibility gene.
Nakayama
J
J
Department of Medical Genetics, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Yamamoto
N
N
Hamano
K
K
Iwasaki
N
N
Ohta
M
M
Nakahara
S
S
Matsui
A
A
Noguchi
E
E
Arinami
T
T
D001714:Bipolar Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008094:Lithium / Q000494:pharmacology; D008126:Lod Score; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D018895:Microsatellite Repeats; D008957:Models, Genetic; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012494:Sampling Studies; D003294:Seizures, Febrile / Q000453:epidemiology / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D018709:Statistics, Nonparametric
D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase