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(Stroke. 2003;34:892.)
© 2003 American Heart Association, Inc.

Original Contributions

Absence of Linkage of Familial Intracranial Aneurysms to 7q11 in Highly Aggregated Japanese Families

Shigeki Yamada, MD; Maki Utsunomiya, MPH; Kayoko Inoue, MD, MPH; Kazuhiko Nozaki, MD, PhD; Susumu Miyamoto, MD, PhD; Nobuo Hashimoto, MD, PhD; Katsunobu Takenaka, MD, PhD; Takeo Yoshinaga, PhD Akio Koizumi, MD, PhD

From the Departments of Neurosurgery (S.Y., K.N., S.M., N.H.) and Health and Environmental Sciences (M.U., K.I., T.Y., A.K.), Kyoto University Graduate School of Medicine, Kyoto; and Department of Neurosurgery, Takayama Red Cross Hospital, Gifu (K.T.), Japan.

Correspondence to Akio Koizumi, MD, PhD, Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. E-mail koizumi{at}pbh.med.kyoto-u.ac.jp

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose— We sought to test the linkage of familial intracranial aneurysms (FIAs) to the ELN (elastin) locus in chromosome 7q11 reported previously.

Methods— Intracranial aneurysm (IA) probands were searched from patient records or neurosurgeons’ recalls in collaborating hospitals. Members of the participating probands’ families who had unknown affection status were screened by MR angiography and diagnosed by digital subtraction angiography. Inclusion criteria of families for genetic analyses were as follows: at least 3 alive affected members or 2 alive affected members with at least 1 unaffected member (60 years). Linkage to the ELN locus was tested with the use of GENEHUNTER by parametric and nonparametric methods. To exclude false-negatives in the linkage analysis, the lowest 5% limits of logarithms of the odds (LOD) and nonparametric LOD (NPL) scores for individual families and for the total set of families were simulated on assumption that the ELN locus is linked to FIAs.

Results— Questionnaires were sent to 885 patients, and 563 responded. Seventy-nine probands were positive for family history. One hundred thirty-four family members of unknown affection status were screened. A total of 14 families with 64 members met the criteria. Linkage to the ELN locus was discarded in 11 families and was inconclusive for 3 families. The total LOD and total NPL scores for 14 families were -8.04 and -0.643, respectively. Our conclusion did not change even when the values of penetrance were changed or only affected members were analyzed.

Conclusions— The majority of aggregated IA Japanese families may not have a genetic linkage to chromosome 7q11.

Key Words: aneurysm, intracranial • elastin • genetics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The annual incidence of subarachnoid hemorrhage (SAH) in the general population is 7 to 25 per 100 000.^1–3 After age 40 years, the incidence in Japan increases to 96 per 100 000 annually, as reported by Kiyohara et al.⁴ SAH is often fatal, and patients who survive the acute phase may suffer a decreased quality of life as a result of major neurological deficits.

The main cause of spontaneous SAH is the rupture of intracranial aneurysms (IAs),⁵ with the prevalence of cerebral aneurysm estimated to be 0.4% to 4.6%.^2,6,7 In Japan, MR angiography (MRA) is widely considered to be a particularly suitable method for screening unruptured IAs. With the use of this method, the prevalence of incidental unruptured IAs in the general population has been reported to be 6% to 7%, but in a subgroup with a family history of IAs it was significantly higher (10.5% to 13.5%).^8,9

Systematic genome-wide searching in regard to IAs has been hampered by 3 main obstacles. First, since SAH is often fatal, it is difficult to obtain large families for genetic analysis. Second, it has been difficult to diagnose the affection status of IAs. Third, age-dependent penetrance cannot exclude misclassifications of potentially affected cases. One approach to solve these problems would be sib-pair analysis. Recently, Onda et al,¹⁰ the first group to conduct a genome-wide linkage study, found a significant linkage of familial intracranial aneurysms (FIAs) to chromosome 7q11 in 104 Japanese affected sib pairs.

The majority of studies that investigated genetic factors for FIAs dealt with aggregated IA families with 2 affected individuals; siblings were the most commonly affected kinship.^10–12 By narrowing the definition of a disease or restricting the patient population, it is often possible to work with a trait that is more nearly mendelian in its inheritance pattern and to decrease disease heterogeneity and eliminate phenocopies.¹¹ On the basis of this idea, we planned to recruit FIAs having a dense aggregation. Although it was fragmentary, several lines of evidence suggested that the percentage with affected members increased close to 50%, as has been reported by others,⁹ or that the inheritance pattern seemed to be autosomal dominant (AD) mode, as has also been reported by others.^12,13 Here we report the genetic analysis of 14 families with dense aggregations of IAs.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Ethical Issues
The Ethics Committee at Kyoto University approved this study. After the appropriate written informed consent was obtained from all participants, blood samples were collected from the family members for the genomic DNA source.

Pedigrees
We recruited probands in 2 different sources (Figure 1). In the first group of probands, probands were searched from patient records in the 8 collaborating hospitals during recent year periods (mean±SD, 6.6±2.2 years) before the start of this study. These probands were diagnosed with ruptured or unruptured saccular IAs by digital subtraction angiography (DSA) and had been treated surgically and discharged alive. We sent questionnaires to probands and asked whether they had family histories of SAH or IA (Figure 2a). If they had family histories, we interviewed probands by telephone regarding family size and details of family history. If they had at least 2 alive affected members, including probands in first-degree relatives, they were asked to join this study. In the second group of probands (families 2, 5, 6, 7, 13), they were recalled by neurosurgeons in the 8 collaborating hospitals. We directly contacted them and asked their families to join this study.

View larger version (49K): [in this window] [in a new window]   Figure 1. FIA pedigrees.

View larger version (25K): [in this window] [in a new window]   Figure 2. Family selection and phenotypic characterization processes.

Pedigree members within the first- or second-degree relatives of the probands and who wished to participate in this study were contacted. MRA was performed in members aged 30 years who did not have confirmed absence of IA within the past 2 years and who agreed to undergo MRA (Figure 2b).

MRA was performed through the whole brain in 3 slabs (thickness=2.4 cm) in the axial plane with 3-dimensional time of flight with a 1.5-T MRI system (Signa Advantage; GE Medical Systems). All MRA examinations were conducted by consensus reading by at least 3 neurosurgeons and supervised by neuroradiologists. If IA was suspected by MRA, DSA was conducted.

None of families were affected with known heritable diseases associated with IA, such as Ehlers-Danlos syndrome type IV, Marfan syndrome, neurofibromatosis type 1, autosomal dominant polycystic kidney disease, or achondroplasia.^12,14,15 No consanguineous marriage was found in the present families.

Genotyping
Genomic DNA was extracted from blood samples with a QIAamp DNA Blood Mini Kit (Qiagen Inc). For the deceased patient (IV-3) in family 5, an umbilical cord was used as the DNA source. Polymerase chain reaction amplification from genomic DNA was performed with fluorescence-labeled (6-FAM, HEX, NED) and tailed primers. The reactions were performed in 7.5 µL with 50 ng genomic DNA by use of AmpliTaq Gold DNA polymerase (PE Applied Biosystems) in a 2-step amplification program. The DNA fragments were analyzed on an ABI Prism 310 Genetic Analyzer. Primers to analyze other polymorphic microsatellite markers were designed according to the information from the Cooperative Human Linkage Center (http://lpg.nci.nih.gov/html-chlc/ChlcMarkers.html) and the Genome Database (http://research. marshfieldclinic.org/genetics/Physical Maps /PhysicalMapPage.htm).

Seven markers spanning 29.4 cM of chromosome 7 were chosen for fine genetic mapping and for identifying the critical interval: D7S519, D7S2467, D7S502, D7S2476, D7S669, D7S2443, and D7S630. These areas covered the ELN (elastin) locus that was reported to link FIAs from a sib-pair analysis.¹⁰

Phenotype Characterization
The criteria for the inclusion of families for genetic analysis were to match 1 of the following 2 conditions: (1) number of alive affected members was at least 3; (2) number of alive affected members was equal to 2 and number of alive unaffected members aged 60 years was at least 1 (Figure 2a). The criteria were chosen because we sought to isolate genetic factors in FIAs without possible contamination of any fortuitous occurrence of sporadic IAs.¹⁶ The rationale for exclusion of unaffected members aged <60 years was to decrease uncertainty in terms of affected status of IAs.^{2–4,6,7,9,17–19} Exceptions were III-5 and III-6 in family 1 and III-7 and III-8 in family 2 (Figure 1). They were included as phenotype "unknown" to reconstruct genotypes of deceased affected members in the genetic analysis. Spouses of II-7 in family 2, II-1 in family 5, and II-1 in family 14 (Figure 1) were included in the linkage analysis with their offspring to reconstruct genotypes of affected deceased members or to decrease phase uncertainty. Spouses were treated as unaffected.

Linkage Analysis
We applied parametric and nonparametric linkage methods to calculated multipoint logarithms of the odds (LOD) score and nonparametric LOD (NPL) score with the GENEHUNTER program (version 2.0).²⁰ The penetrance for individuals aged 60 years was estimated to be 0.9, the prevalence of incidental IAs was estimated to be 0.02,² and the disease gene frequency was estimated to be approximately 0.01 in the general population. When specified, we changed penetrance to 0.8 or 0.7. Sensitivity analyses revealed that multipoint LOD and NPL scores were not sensitive to any change in the prevalence of IA phenocopy (0.01, 0.02, 0.04) or the disease gene frequency (0.001 to 0.01). We thus presented the data under conditions of a prevalence of IA phenocopy=0.02 and a disease gene frequency=0.01 in the general population. The test for locus heterogeneity was performed with the HOMOG program.²¹ Two-point LOD scores were calculated with the MLINK program.²² The level of suggestive linkage for LOD score was chosen at 1.9,²³ and that for NPL score was 2.5.

Computer Simulation
We simulated multipoint LOD and NPL scores for a region from D7S519 to D7S630 (29.4-cM) on chromosome 7 in each family by computer simulation. In the program, we simulated recombination events in a 29.4-cM fragment between D7S519 and D7S630 and located the ELN locus between D7S2476 and D7S669. The simulation was run 300 times unless otherwise specified. If multipoint LOD scores (or NPL scores) of individual families actually observed were smaller than the lowest 5% values of simulated scores, they were considered to indicate the absence of linkage.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Pedigrees
A total of 885 patients (326 males and 559 females) received by mail questionnaires about any family histories of SAH or IAs. Of these, 563 (209 males and 354 females) responded, and 79 (36 males and 43 females) were found to have positive family histories (14.0%) (Figure 2a). Finally, 9 families (families 1, 3, 4, 8 to 12, 14) recruited from questionnaires and 5 families (families 2, 5, 6, 7, 13) recalled by neurosurgeons made up the set of families (Figure 1).

In 14 families, 134 members were aged 30 years and could be contacted. Among them, 71 wished to join this study (Figure 2b). A total of 71 blood relatives in these 14 families were screened by MRA. MRA screening and subsequent DSA found incidental IAs in 14 (20%) members. Among 45 members of known affection status, 34 were alive and 11 were deceased. Genotypes in 4 of 11 deceased affected members were reconstructed for genetic analyses. In these affected members, affection status was confirmed as history of clipping surgery by 1 of 3 methods: review of medical records, interview of the participants, or interview of patients’ relatives.

Clinical characterizations of affected members are summarized in Table 1. After screening and DSA diagnoses, 7 of 20 members (aged 60 years) (35.0%) and 7 of 51 members (aged <60 years) (13.7%) were found to have IAs. In total, 38 known affected, 14 newly diagnosed, and 12 unaffected members were analyzed (Figure 2b).

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characterization of Affected Members

View this table: [in this window] [in a new window]   TABLE 1. Continued

Power
Because of differences in sizes of families and possible locus heterogeneities among families, it was difficult to estimate the power of the present family set. We estimated the power of the present family set under the most pessimistic condition that only the smallest families were linked to the ELN locus. Under this scenario, we calculated the number of families necessary to prove a suggestive linkage level (LOD score=1.9). In this simulation, we totaled LOD and NPL scores of individual families. The simulation (3000 times) revealed that if the 8 smallest families (families 4, 5, 7 to 11, 14) were linked to the ELN locus, the power to obtain an LOD score of 1.9 was 0.97. If the 7 smallest families (families 4, 7 to 11, 14) were linked, the power was 0.93. Under these conditions, the probability of false-positive linkage for these families was <0.01. The corresponding power of NPL score (2.5) was 0.62 for 8 families and 0.57 for 7 families, respectively. If larger families were linked to the ELN locus, smaller numbers of families were enough to obtain similar powers.

Linkage Analysis
We tested whether the reported ELN locus on chromosome 7q11 may have a significant linkage with IAs found in the 14 families. As shown (Figure 1), inheritance patterns seem to be in accord with an AD mode in 10 families (families 1, 2, 4 to 7, 10, 11, 13, 14). We thus used the AD mode for parametric analysis. We also calculated NPL scores, which are independent of mode of inheritance,²⁰ in parallel to avoid any possible bias in the mode of inheritance. We calculated multipoint LOD and NPL scores for individual families with a 29.4-cM region in chromosome 7 spanning from D7S519 to D7S630, in which the ELN locus was between D7S2476 and D7S669 (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Simulated and Observed Multipoint LOD and NPL Scores for a 29.4-cM Region on Chromosome 7*

For evaluation of the linkages in individual families, we used the following rule. For families suspected of AD mode, LOD scores were weighed more than NPL scores for judging linkages, while for families in which the mode was unknown, the reverse was the case. These values were compared with the lowest 5% of corresponding values for individual families (Table 2).

Observed LOD scores in the 8 families (families 1, 2, 4 to 7, 13, 14) in which IAs were inherited in AD mode were less than the lowest 5% of the simulated multipoint LOD scores under the assumption that the ELN locus was linked to IAs. Observed NPL scores in 4 families (families 3, 8, 9, 12) in which IAs were inherited in undetermined mode were less than the lowest 5% of the simulated multipoint NPL scores under the assumption that the ELN locus was linked to IAs. On the other hand, it remains inconclusive whether 2 families, families 10 and 11, were linked to the ELN locus. The total observed maximum multipoint LOD (-8.04) and NPL (-0.64) scores for the entire family set were also below the lowest 5% of the total simulated multipoint LOD (6.17) and NPL (3.13) scores.

Two-point LOD scores (=0) were negative in all families for D7S502 except families 6 (0.34), 8 (0.28), 10 (0.14), and 11 (0.28) for D7S2476 and except families 3 (0.63) and 8 (0.1) for D7S669 (data not shown). Total 2-point LOD scores (=0) were -9.99 for D7S502, -1.01 for D7S2467, and -9.47 for D7S669. The marker D7S2476 was not informative because of a low heterogeneity index (0.473) and thus was not reliable. We tested locus heterogeneity using the HOMOG program. The results indicated an absence of linkage to the ELN locus.

Sensitivity Analyses
In the present study we assumed penetrance as 0.9 in persons aged 60 years. Penetrance theoretically has a great influence on LOD scores, while it does not have influence on NPL scores. However, penetrance is difficult to determine. We thus conducted sensitivity analyses to investigate the robustness of our results. In sensitivity analyses, penetrance changed from 0.9 to 0.8 or 0.7. Changes in penetrance seemed to have little effect on the results (Table 2; results at penetrance=0.8 are not shown). One major reason for the robustness of penetrance was that participants in the linkage analyses were primarily affected members (52/64=0.81).

Affected-Members-Only Linkage Analyses
Affected-members-only linkage analyses of all 14 families did not change the major portion of results except for the LOD score of family 4. We tested the possibility that families 4, 10, and 11 may be linked to the ELN locus. We then reanalyzed linkages with only affected members in families 4, 10, and 11. Even given that these 3 families had been linked, the power was not large enough (maximum expected LOD score=0.99 and NPL score=1.80) to test linkage to the ELN locus. Thus, results for these 3 families remained inconclusive.

Taken together, the present results may not consistently support the notion that the ELN locus is involved in IAs in the majority of the present families, although a linkage in 3 families (families 4, 10, 11) could not be dismissed.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The hypothesis that genetic factors play a role in the development of IAs is supported by various studies that have observed a higher prevalence of IAs in healthy first-degree family members.^8,9,16

There is an emerging interest in analyzing candidate genes on the basis of the hypothesis that genetic variants may be associated with the occurrence of IAs. Candidate genes thus far examined include versatile functional molecules.^24–31 The association of IAs with these candidate genes has not been confirmed consistently. Competitive evidence suggests limitations for the candidate gene approach.

Onda et al¹⁰ showed striking evidence demonstrating a linkage of the IA gene on chromosome 7q11 by their genome-wide search. They chose sib-pair analysis as a mapping strategy and analyzed 104 affected Japanese sib pairs. With the aid of single nucleotide polymorphisms, they successfully narrowed the linked area to the ELN locus. In contrast, the majority of our aggregated IA families (at least 11 of 14) did not show evidence of any linkage to a 29.4-cM fragment containing the ELN locus, although the linkage was inconclusive in the remaining 3 families (families 4, 10, 11).

Several possibilities may explain the discrepancy. We used parametric and nonparametric methods, while Onda et al¹⁰ used only a nonparametric method, sib-pair analysis. Sib-pair analysis is somewhat robust regarding the model parameters and the degrees of locus heterogeneities among sib pairs. In contrast, the present parametric method is sensitive to penetrance and the mode of inheritance but can evaluate locus heterogeneities. First, penetrance, which is difficult to determine for late-onset traits, is an influential parameter in parametric analysis but not in nonparametric analysis. We therefore conducted sensitivity analyses. Sensitivity analyses did not change our conclusion when penetrance was changed from 0.9 to 0.7. Second, although IAs were transmitted in AD mode in the majority of families, there may still be uncertainty regarding the mode of inheritance. To evaluate the effects of this uncertainty, we evaluated linkages by NPL score, which is independent of the mode of inheritance.²⁰ NPL scores did not change our major conclusion. However, the power of the nonparametric method in the present study was limited. For example, the power is 57% if only the smallest 7 families are linked to the ELN locus, suggesting that there is a >40% chance that we may have missed a linkage using nonparametric testing. Although this scenario may be pessimistic, this is one of the limitations of the present study.

The present study has other limitations. We used MRA as a screening tool for IAs. This method has limitations for accuracy of diagnosis. It is well known that many factors, including size, location, and manner of reading (consensus or not), may influence the various degrees of sensitivities and may result in a misclassification of affected phenotypes and unaffected phenotypes. It has been reported that the sensitivity of MRA ranged from 0.76 to 0.98³² and 0.92 with consensus reading.³³ We estimated sensitivity as 0.9 in this study, expecting that 1 or 2 of the 12 unaffected persons might be misclassified. To evaluate this uncertainty, linkage analyses with only affected members were conducted. These analyses, however, confirmed an absence of linkage in 11 of the 14 families and resulted in inconclusive results for 3 of the families (families 4, 10, 11). Second, because selected probands had been discharged alive, a selection bias of probands may contaminate the results. However, this selection process was performed in random fashion in view of genetic factors because at present we do not know disease heterogeneity or locus heterogeneity.³⁴ An essential solution for this problem would be an increase in the number of families. An approach is currently being pursued.

Families with only 2 affected members are the most common pattern (>75%).^12,35 Even aggressive screening could not find new affected members with IAs in 50% of the families with only 2 affected members.¹⁶ Families with apparently only 2 affected members may therefore be genetically heterogeneous.

Although there are several limitations of the present study, our results suggest that the ELN locus on 7q11 may not be the major locus linked to highly aggregated Japanese IA families. Genome-wide searching for unknown IA genes with a large pedigree consortium is therefore still a worthwhile pursuit, albeit one that needs extensive effort.

	Acknowledgments

 
This work was supported by a grant from the Japanese Ministry of Education, Science, Sports, and Culture (12557034, 12470081, 14207016). This project was also supported by a grant in aid from the Ministry of Welfare and Labor (H11-Chojyu010). We would like to thank the family members for participating in this study and the following consortium members for introducing them: S. Nagasawa and J. Mabuchi (Soseikai General Hospital), Y. Tokuriki and T. Tokime (Fukui Red Cross Hospital), S. Sugimoto and T. Iwata (Geroonsen Hospital), S. Yamagata and M. Hojo (Kurashiki Centeral Hospital), T. Kaneko and N. Murai (Hikone Municipal Hospital), H. Yamakawa and T. Iwamoto (Gifu Municipal Hospital), Y. Uemura and A. Fujita (Maizuru Municipal Hospital), A. Okumura and N. Matsuura (Kyoto Municipal Hospital), Y. Akiyama and H. Yukawa (Shiga Medical Center for Adults), I. Nagata and T. Higashi (National Cardiovascular Center), and S. Yoneda and Y. Naruo (Nihonbashi Hospital).

Received August 6, 2002; revision received September 25, 2002; accepted October 2, 2002.

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