Genome screen in familial intracranial aneurysm.
BACKGROUND
Individuals with 1st degree relatives harboring an intracranial aneurysm (IA) are at an increased risk of IA, suggesting genetic variation is an important risk factor.


METHODS
Families with multiple members having ruptured or unruptured IA were recruited and all available medical records and imaging data were reviewed to classify possible IA subjects as definite, probable or possible IA or not a case. A 6 K SNP genome screen was performed in 333 families, representing the largest linkage study of IA reported to date. A 'narrow' (n = 705 definite IA cases) and 'broad' (n = 866 definite or probable IA) disease definition were used in multipoint model-free linkage analysis and parametric linkage analysis, maximizing disease parameters. Ordered subset analysis (OSA) was used to detect gene x smoking interaction.


RESULTS
Model-free linkage analyses detected modest evidence of possible linkage (all LOD < 1.5). Parametric analyses yielded an unadjusted LOD score of 2.6 on chromosome 4q (162 cM) and 3.1 on chromosome 12p (50 cM). Significant evidence for a gene x smoking interaction was detected using both disease models on chromosome 7p (60 cM; p </= 0.01). Our study provides modest evidence of possible linkage to several chromosomes.


CONCLUSIONS
These data suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms.
Foroud
Tatiana
T
Indiana University School of Medicine, Indianapolis, IN, 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
Langefeld
Carl
C
Rouleau
Guy
G
Connolly
E Sander
ES
Lai
Dongbing
D
Koller
Daniel L
DL
Huston
John
J
Broderick
Joseph P
JP
D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D002532:Intracranial Aneurysm / Q000209:etiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects