Genome screen to detect linkage to intracranial aneurysm susceptibility genes: the Familial Intracranial Aneurysm (FIA) study.
OBJECTIVE
Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA.


METHODS
Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene x smoking (pack-years) interaction.


RESULTS
The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking.


CONCLUSIONS
We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene x smoking interaction with 3 of the loci.
Foroud
Tatiana
T
Indiana University School of Medicine, Health Information and Translational Sciences Building - HS 4000, 410 West 10th Street, Indianapolis, IN 46202-3002, USA. tforoud@iupui.edu
Sauerbeck
Laura
L
Brown
Robert
R
Anderson
Craig
C
Woo
Daniel
D
Kleindorfer
Dawn
D
Flaherty
Matthew L
ML
Deka
Ranjan
R
Hornung
Richard
R
Meissner
Irene
I
Bailey-Wilson
Joan E
JE
Rouleau
Guy
G
Connolly
E Sander
ES
Lai
Dongbing
D
Koller
Daniel L
DL
Huston
John
J
Broderick
Joseph P
JP
D000328:Adult; D002874:Chromosome Mapping / Q000379:methods; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D016678:Genome / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007391:International Cooperation; D002532:Intracranial Aneurysm / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D013345:Subarachnoid Hemorrhage / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology