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PubMed1993

Evidence for linkage of the gene causing familial Mediterranean fever to chromosome 17q in non-Ashkenazi Jewish families: second locus or type I error?

Familial Mediterranean fever (FMF) is an autosomal recessive disorder of unknown pathogenesis, characterized by recurrent, self-limited attacks of fever with synovitis, peritonitis, or pleurisy. Using DNAs from affected Israeli families, we have recently mapped the gene causing FMF (designated MEF) to the short arm of chromosome 16, with two-point lod scores in excess of 20. In this report we consider the possibility of a second FMF susceptibility locus. Before discovering linkage to markers on chromosome 16, we had found suggestive evidence for linkage to chromosome 17q, with the following maximal two-point lod scores: D17S74 (pCMM86), Z = 2.47, (theta = 0.20); D17S40 (pLEW101), Z = 2.15 (theta = 0.15); D17S35 (CRI-pP3-1), Z = 1.78 (theta = 0.15); D17S46 (pLEW108), Z = 1.69 (theta = 0.18), D17S254, Z = 2.30 (theta = 0.20). Moreover, multipoint linkage analysis using D17S74 and D17S40 as fixed loci gave Z = 3.27 approximately 10 centimorgans (cM) telomeric to D17S40. Data with the chromosome 17 markers alone in our families suggested locus heterogeneity. Nevertheless, our families were not separable into complementary subsets showing linkage either to chromosome 16 or to chromosome 17. We also examined the possibility that the positive lod scores for chromosome 17 might reflect a secondary, modifying locus. By several measures of disease severity, families with positive lod scores for chromosome 17 loci had no worse disease than those with negative lod scores for these loci. We conclude that chromosome 17 does not encode a major FMF susceptibility gene for some of the families, nor does it encode a disease-modifying gene. Rather, it would appear that linkage to chromosome 17 is a "false positive" (type I) error. These results reemphasize the fact that a lod score of 3.0 corresponds to a posterior probability of linkage of 95%, with an attendant 1 in 20 chance of observing a false positive.

Blotting, Southern↗

PubMed1982

The effects of requisite assumptions on linkage analyses of manic-depressive illness with HLA.

Two large pedigrees with a bipolar proband were selected on the basis of compatibility with the hypothesis of autosomal dominant inheritance of a depressive taxon. We compared the results of linkage analyses of the depressive taxon with HLA and GLO in these pedigrees when penetrance function, diagnostic classification, and HLA haplotype frequencies were varied. The analyses show that all three types of assumptions affect the lod scores and likelihoods obtained. Using the most favorable assumptions, we obtain a lod score of 3.901 at theta = 0.10 for HLA with the depressive taxon. This lod score would conventionally be considered strong evidence of linkage of a subtype of manic-depressive illness with HLA but the dependence of these results on several untested assumptions suggests more cautious interpretation. Nonetheless, we feel it does represent evidence in favor of linkage because this high a lod score cannot readily be dismissed as statistical artifact. The results point out the importance of careful delineation of the assumptions made in linkage analyses of complex disorders, including the diagnostic criteria, marker allele frequencies, and age-of-onset function used.

Adolescent↗

PubMed1999

A genome search identifies major quantitative trait loci on human chromosomes 3 and 4 that influence cholesterol concentrations in small LDL particles.

Small, dense LDL particles are associated with increased risk of cardiovascular disease. To identify the genes that influence LDL size variation, we performed a genome-wide screen for cholesterol concentrations in 4 LDL size fractions. Samples from 470 members of randomly ascertained families were typed for 331 microsatellite markers spaced at approximately 15 cM intervals. Plasma LDLs were resolved by using nondenaturing gradient gel electrophoresis into 4 fraction sizes (LDL-1, 26.4 to 29.0 nm; LDL-2, 25.5 to 26.4 nm; LDL-3, 24.2 to 25.5 nm; and LDL-4, 21.0 to 24.2 nm) and cholesterol concentrations were estimated by staining with Sudan Black B. Linkage analyses used variance component methods that exploited all of the genotypic and phenotypic information in the large extended pedigrees. In multipoint linkage analyses with quantitative trait loci for the 4 fraction sizes, only LDL-3, a fraction containing small LDL particles, gave peak multipoint log10 odds in favor of linkage (LOD) scores that exceeded 3.0, a nominal criterion for evidence of significant linkage. The highest LOD scores for LDL-3 were found on chromosomes 3 (LOD=4.1), 4 (LOD=4.1), and 6 (LOD=2.9). In oligogenic analyses, the 2-locus LOD score (for chromosomes 3 and 4) increased significantly (P=0.0012) to 6.1, but including the third locus on chromosome 6 did not significantly improve the LOD score (P=0.064). Thus, we have localized 2 major quantitative trait loci that influence variation in cholesterol concentrations of small LDL particles. The 2 quantitative trait loci on chromosomes 3 and 4 are located in regions that contain the genes for apoD and the large subunit of the microsomal triglyceride transfer protein, respectively.

Adolescent↗

PubMed1999

Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity.

Several loci and candidate genes for epilepsies or epileptic syndromes map or have been suggested to map to chromosome 8. We investigated families with adolescent-onset idiopathic generalized epilepsy (IGE), for linkage to markers spanning chromosome 8. The IGEs that we studied included juvenile myoclonic epilepsy (JME), epilepsy with only generalized tonic-clonic seizures occurring either randomly during the day (random grand mal) or on awakening (awakening grand mal), and juvenile absence epilepsy (JAE). We looked for a gene common to all these IGEs, but we also investigated linkage to specific subforms of IGE. We found evidence for linkage to chromosome 8 in adolescent-onset IGE families in which JME was not present. The maximum multipoint LOD score was 3.24 when family members with IGE or generalized spike-and-waves (SW) were considered affected. The LOD score remained very similar (3.18) when clinically normal family members with SW were not considered to be affected. Families with either pure grand mal epilepsy or absence epilepsy contributed equally to the positive LOD score. The area where the LOD score reaches the maximum encompasses the location of the gene for the beta3-subunit of the nicotinic acetylcholine receptor (CHRNB3), thus making this gene a possible candidate for these specific forms of adolescent-onset IGE. The data excluded linkage of JME to this region. These results indicate genetic heterogeneity within IGE and provide no evidence, on chromosome 8, for a gene common to all IGEs.

Adolescent↗

PubMed1992

Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16.

BACKGROUND: Familial Mediterranean fever is an autosomal-recessive disease characterized by acute attacks of fever with sterile peritonitis, pleurisy, or synovitis. The biochemical basis of the disease is unknown, but determining the chromosomal location of the gene for the disorder should be a first step toward defining the biochemical events. METHODS AND RESULTS: As part of a systematic genome-wide search, we sought evidence of linkage between familial Mediterranean fever and chromosome 16 DNA markers in 27 affected non-Ashkenazi Jewish families from Israel. Two loci from the subtelomeric region of the short arm of chromosome 16 (16p) had lod scores sufficient to establish linkage (a score greater than or equal to 3). One DNA marker (D16S84) gave a maximal lod score of 9.17 (odds of 10(9.17) to 1 in favor of linkage) at a recombination frequency (theta) of 0.04. A probe associated with the hemoglobin alpha complex (5'HVR) gave a maximal lod score of 14.47 at a theta of 0.06. Multipoint linkage analysis indicated that the following was the most likely gene order: the centromere, the gene for familial Mediterranean fever, D16S84, hemoglobin alpha, and the telomere. The maximal multipoint lod score was 19.86. There was a striking degree of homozygosity at chromosome 16p loci in the affected offspring of eight consanguineous couples. CONCLUSIONS: The gene that causes familial Mediterranean fever in non-Ashkenazi Jews maps to the short arm of chromosome 16.

Centromere↗

PubMed2000

Power comparison of parametric and nonparametric linkage tests in small pedigrees.

When the mode of inheritance of a disease is unknown, the LOD-score method of linkage analysis must take into account uncertainties in model parameters. We have previously proposed a parametric linkage test called "MFLOD," which does not require specification of disease model parameters. In the present study, we introduce two new model-free parametric linkage tests, known as "MLOD" and "MALOD." These tests are defined, respectively, as the LOD score and the admixture LOD score, maximized (subject to the same constraints as MFLOD) over disease-model parameters. We compared the power of these three parametric linkage tests and that of two nonparametric linkage tests, NPLall and NPLpairs, which are implemented in GENEHUNTER. With the use of small pedigrees and a fully informative marker, we found the powers of MLOD, NPLall, and NPLpairs to be almost equivalent to each other and not far below that of a LOD-score analysis performed under the assumption the correct genetic parameters. Thus, linkage analysis is not much hindered by uncertain mode of inheritance. The results also suggest that both parametric and nonparametric methods are suitable for linkage analysis of complex disorders in small pedigrees. However, whether these results apply to large pedigrees remains to be answered.

Chromosome Mapping↗

PubMed1996

Mapping of autosomal dominant cone degeneration to chromosome 17p.

PURPOSE: We studied a single, large family with autosomal dominant cone degeneration in order to map the disease-causing gene. METHODS: Seventy-three individuals in this family were examined, and 34 were found to be affected. Blood samples from 34 affected and unaffected family members were obtained for DNA analysis and linkage mapping. Fifty-three genetic markers were analyzed in this family by using short tandem repeat markers. These markers were primarily in candidate genomic regions. RESULTS: Marker D17S796 generated a significantly positive LOD score of 4.21 (theta = .04; 10,000:1 odds in favor of linkage). Marker D17S513 gave a significant LOD score of 3.1 (theta = .096; 1,000:1 odds in favor of linkage). Other markers in the region generated suggestive findings, such as D17S786, with a LOD score of 2.7, and D17S945, with a LOD score of 2.41. CONCLUSIONS: Our results indicate that a genetic defect that causes autosomal dominant cone degeneration is located on chromosome 17p in the region of recoverin. Recoverin, a retinal expressed gene, is an appealing candidate for this disease.

Adolescent↗

PubMed2005

Ordered subset analysis supports a glaucoma locus at GLC1I on chromosome 15 in families with earlier adult age at diagnosis.

Open angle glaucoma (OAG) is a complex disorder with varying etiologies due to multiple genes and environmental effects. This genetic heterogeneity can confound efforts to map loci. Increased homogeneity in a sample can be achieved using either ordered subset analysis (OSA) which groups families, or individual OSA (IOSA), which groups individuals based on disease related covariates. Recently, GLC1I was mapped to 15q11-13 in families with early adult onset of OAG. We tested for linkage to GLC1I in an independent sample of 167 individuals in 25 multiplex OAG families of European descent. We carried out nonparametric linkage analysis on the complete set of 25 families and obtained a maximum LOD score of 1.00 at 9.0 cM. Using mean age at diagnosis (AAD) across the affected individuals within each family to order the families as a proxy for age at onset, we found a maximum OSA LOD score of 2.09 (p=0.021) at 26.1 cM. The mean (+/-s.d.) AAD across the 14 earlier AAD families that contributed to the OSA LOD score was 50.6 years (+/-5.38); the mean AAD for the other 1210 later AAD families that did not contribute to the OSA LOD score (the high-AAD) was 61.7 years (+/-3.50). We also ran IOSA on our families using AAD as our covariate on which to subset affected individuals. The maximum LOD score was 1.01 at 14.3 cM when ordering subjects from early to late AAD. Ordered subset analysis of this sample has provided evidence of linkage close to the previously identified GLC1I glaucoma locus on 15q11-13 in families with middle-aged mean age at diagnosis.

Adolescent↗

PubMed1997

A linkage study across the T cell receptor A and T cell receptor B loci in families with rheumatoid arthritis.

OBJECTIVE: To examine whether the T cell receptor (TCR) A or TCRB loci exhibit linkage with disease in multiplex rheumatoid arthritis (RA) families. METHODS: A linkage study was performed in 184 RA families from the UK Arthritis and Rheumatism Council Repository, each containing at least 1 affected sibpair. The microsatellites D14S50, TCRA, and D14S64 spanning the TCRA locus and D7S509, Vbeta6.7, and D7S688 spanning the TCRB locus were used as DNA markers. The subjects were genotyped using a semiautomated polymerase chain reaction-based method. Two-point and multipoint linkage analyses were performed. RESULTS: Nonparametric single-marker likelihood odds (LOD) scores were 0.49 (P = 0.07) for D14S50, 0.65 (P = 0.04) for TCRA, 0.07 (P = 0.29) for D14S64, 0.01 (P = 0.43) for D7S509, 0.0 (P = 0.50) for Vbeta6.7, and 0.0 (P = 0.50) for D7S688. By multipoint analysis, there was no evidence of linkage at TCRB (LOD score 0), and the maximum LOD score at the TCRA locus was 0.37 (at D14S50). The presence of a susceptibility locus (LOD score < -2.0) was excluded, with lambda > or = 1.8 at TCRA and > or = 1.4 at TCRB. CONCLUSION: These linkage studies provide no significant evidence of a major germline-encoded TCRA or TCRB component of susceptibility to RA.

Alleles↗

PubMed1996

The problem of ascertainment for linkage analysis.

It is generally believed that ascertainment corrections are unnecessary in linkage analysis, provided individuals are selected for study solely on the basis of trait phenotype and not on the basis of marker genotype. The theoretical rationale for this is that standard linkage analytic methods involve conditioning likelihoods on all the trait data, which may be viewed as an application of the ascertainment assumption-free (AAF) method of Ewens and Shute. In this paper, we show that when the observed pedigree structure depends on which relatives within a pedigree happen to have been the probands (proband-dependent, or PD, sampling) conditioning on all the trait data is not a valid application of the AAF method and will result in asymptotically biased estimates of genetic parameters (except under single ascertainment). Furthermore, this result holds even if the recombination fraction R is the only parameter of interest. Since the lod score is proportional to the likelihood of the marker data conditional on all the trait data, this means that when data are obtained under PD sampling the lod score will yield asymptotically biased estimates of R, and that so-called mod scores (i.e., lod scores maximized over both R and parameters theta of the trait distribution) will yield asymptotically biased estimates of R and theta. Furthermore, the problem appears to be intractable, in the sense that it is not possible to formulate the correct likelihood conditional on observed pedigree structure. In this paper we do not investigate the numerical magnitude of the bias, which may be small in many situations. On the other hand, virtually all linkage data sets are collected under PD sampling. Thus, the existence of this bias will be the rule rather than the exception in the usual applications.

Bias↗

PubMed1998

Quantitative trait loci for blood glucose confirm diabetes predisposing and protective genes, Iddm4 and Iddm5r, in the spontaneously diabetic BB/OK rat.

Several crossing studies using diabetic BB/OK and diabetes-resistant rat strains have clearly shown that the MHC class-II-genes of the RT1u haplotype (Iddm1) and the lymphopenia (Iddm2) are essential but not sufficient for type 1 diabetes development. The search for additional diabetogenic genes revealed predisposing non-MHC genes, Iddm3 and Iddm4, and a diabetes protective gene, Iddm5r, cosegregating with diabetes in the BB/OK rat subline. These findings were based on cosegregation studies comparing allele frequencies between diabetic and non-diabetic cross hybrids. Since, type 1 diabetes is characterised by hyperglycaemia we analysed 22 diabetic and 43 non-diabetic [(BB x SHR)FI x BB] backcross hybrids (28M:37F) which were already homozygous for Iddml and Iddm2 to search for quantitative trait loci (QTLs) affecting blood glucose in BB/OK rats. The QTL analysis using 117 microsatellite markers located on 19 autosomal chromosomes and the X chromosome, revealed suggestive linkage for blood glucose at the same position for diabetics (lod score 3.1) and non-diabetics at an age of 16 weeks at locus D6Mgh2 on chromosome 6 (lod score 1.9). In contrast, the peak for nondiabetics at an age of 28 weeks (lod score 3.1) was located in the region on chromosome 1 flanked by D1Mgh12 and D1Mit14, whereas the peak for diabetics (lod score 1.9) was found between Sa and Igf2. The distance between two peaks is ca. 50 cM. These findings are consistent with previously described results and provide strong evidence on the relevance of the described region for the development of diabetes not only in the rat, but, regarding the chromosomal homology also in human.

Animals↗

PubMed2002

Genomic screen and follow-up analysis for autistic disorder.

Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant impairment in social, communicative, and behavioral functioning. A genetic basis for AutD is well established with as many as 10 genes postulated to contribute to its underlying etiology. We have completed a genomic screen and follow-up analysis to identify potential AutD susceptibility loci. In stage one of the genome screen, 52 multiplex families (two or more AutD affected individuals/family) were genotyped with 352 genetic markers to yield an approximately 10 centimorgan (cM) grid, inclusive of the X chromosome. The selection criterion for follow-up of interesting regions was a maximum heterogeneity lod score (MLOD) or a maximum nonparametric sib pair lod score (MLS) of at least 1.0. Eight promising regions were identified on chromosomes 2, 3, 7, 15, 18, 19, and X. In the stage two follow-up study we analyzed an additional 47 multiplex families (total=99 families). Regions on chromosomes 2, 3, 7, 15, 19, and X remained interesting (MLOD> or =1.0) in stage two analysis. The peak lod score regions on chromosomes 2, 7, 15, 19, and X overlap previously reported peak linkage areas. The region on chromosome 3 is unique.

Adult↗

PubMed1994

Analysis of chromosome 22 markers in nine schizophrenia pedigrees.

Previous results of a genome-wide survey for schizophrenia susceptibility genes in nine multiplex families indicated a possible region of linkage on chromosome 22. We therefore tested for linkage using ten highly polymorphic chromosome 22 DNA markers. Lod score analyses were suggestive of linkage for several markers on the distal end of the chromosome; however, no lod score exceeded 3 assuming either autosomal dominant or autosomal recessive transmission. The highest lod score was 2.09 (theta = 0.10) for marker D22S276 under autosomal recessive inheritance. Based on simulation analyses, this result is unlikely to represent a false positive. Analyses using information from affected individuals only resulted in reduced lod scores, with a maximum of 1.40 (theta = 0.05) for D22S276 assuming autosomal recessive inheritance. Two nonparametric methods, sib pair analysis and the Affected-Pedigree-Member method, also yielded suggestive but inconclusive findings; results were positive, but strict thresholds of significance were not met. Additionally, we tested one candidate gene, the Arylsulfatase A gene, located in the region of 22q13.31-qter. Results were again inconclusive, though the DNA marker available for this gene was a 2-allele RFLP with heterozygosity of 0.5, and therefore not maximally informative. Further investigation of this chromosomal region and this and other candidate genes may be warranted.

Adolescent↗

PubMed1986

Linkage analysis of Von Recklinghausen neurofibromatosis: chromosomes 4 and 19.

This report describes a study that examines the hypotheses of genetic linkage between the autosomal dominant disorder neurofibromatosis (NF) and loci on human chromosomes 4 and 19. Twelve Utah families were evaluated for evidence of possible linkage of NF to six known markers on chromosome 4 and five markers on chromosome 19. Due to previous reports suggesting tight linkage of NF to the GC locus on chromosome 4 and the C3 (linked to myotonic dystrophy) locus on chromosome 19, these two markers were of particular interest. For the Utah families the cumulative LOD score for GC was -4.81 (r = 0.05). Cumulative LOD scores were -0.90 (r = 0.05) and -1.01 (r = 0.05) for C3 serum determinations and a C3 DNA polymorphism respectively. Linkage data is also included on all individual informative families for the GC and C3 loci to specifically address the question of heterogeneity. Linkage data is consistent with, but does not strongly support, the existence of heterogeneity implicating both the GC locus on chromosome 4 and the C3 locus on chromosome 19. A compilation of cumulative LOD scores from this and other current linkage studies produces values that in the absence of heterogeneity refute previous reports for tight linkage of NF to GC and to C3.

Adolescent↗

PubMed2006

Genome-wide linkage scan for spontaneous DZ twinning.

In humans, spontaneous DZ twinning is known to have a genetic basis. A prior investigation in the Flemish and Dutch population showed that the phenotype of 'having DZ twins' was consistent with an autosomal monogenic dominant model, with a gene frequency of 3.5% and a female-specific lifetime penetrance of 10%. Recessive, X-linked, polygenic and sporadic models were rejected. This study reports on a genome-wide scan of 14 Flemish families containing 57 mothers of spontaneous DZ twins. Two-point linkage analysis using the autosomal dominant model showed nine chromosomal regions with a LOD score around 1. After multipoint linkage analysis, including heterogeneity, three chromosomes continued to give high LOD scores. These regions were further haplotyped with additional markers at 1 cM distance. The multipoint analysis was not in favour of linkage of the DZ twinning trait in most candidate genes and other regions (LOD score < -2) under the genetic model of autosomal dominance. To further evaluate the evidence for linkage given some uncertainty about the correct mode of inheritance of twinning susceptibility other models of inheritance were tested. Results of this analysis showed all models gave highest LOD scores under dominant models. If heterogeneity among the families is taken into account, the peaks that were observed on chromosome 2, 7 and 18 could well contain a potential gene contributing to DZ twinning. These results give suggestive evidence that the mode of inheritance of DZ twinning is probably more complex than was originally expected.

Belgium↗

PubMed2005

Evidence for a gene influencing high-density lipoprotein cholesterol on chromosome 4q31.21.

OBJECTIVE: A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary atherosclerosis. To identify novel genes regulating plasma HDL-C levels, we investigated 13 multigenerational French Canadian families with an average of 12 affected individuals per family for genome-wide signals, which we subsequently fine mapped. METHODS AND RESULTS: We genotyped a total of 362 individuals, including 151 affected subjects for 485 autosomal microsatellite markers. In parametric 2-point linkage analyses, the highest 2-point logarithm of odds (lod) score of 4.6 was observed with marker D4S424 on chromosome 4q31.21 (at approximately 142 Mb). The multipoint analysis of this region resulted in a lod score of 3.8 and a lod -1 region of 12.2 cM, containing 40 known genes. The results were obtained by allowing for genetic heterogeneity among these extended pedigrees, and approximately 50% of families were linked to this region with the highest single-pedigree lod score being 3.6. We further restricted the linked region from 12.2 to 2.9 cM (2.37 Mb) by genotyping 15 additional markers in the 3 families with the highest lod scores. We sequenced 4 genes with a likely role in lipid metabolism as well as 2 genes residing directly under the linkage peak but found no evidence for a causative variant. None of the genes residing in the significantly restricted 2.37-Mb region has been associated previously with HDL-C metabolism. CONCLUSIONS: This study provides significant evidence for a gene influencing HDL-C on chromosome 4q31.21.

Canada↗

PubMed2004

The search for genetic risk factors associated with suicidal behavior.

BACKGROUND: Suicide and suicidal behavior are prevalent among individuals with psychiatric disorders, including alcohol dependence. A genome screen was performed in multiplex alcohol dependent families ascertained as part of the Collaborative Study on the Genetics of Alcoholism to identify chromosomal regions of interest related to two types of suicidal behavior: suicide attempts and suicidality. METHODS: Sibling pair analyses were used to conduct linkage analyses using both qualitative and quantitative suicide-related phenotypes. The qualitative trait of "suicide attempts" was examined using 59 affected sibling pairs. The quantitative trait of "suicidality" was examined using all possible 1366 sibling pairs and 705 independent sibling pairs. RESULTS: For the qualitative phenotype suicide attempts, chromosome 2 yielded a maximum lod score of 4.2. For the quantitative suicidality index, a maximum lod score of 1.8 was observed on chromosome 3, and a lod score of 1.5 was found on chromosome 1. CONCLUSIONS: This study represents the first genome-wide scan of suicidal behavior. Significant evidence of linkage was found on chromosome 2 for the phenotype suicide attempts, the same chromosomal region previously reported to be linked to alcohol dependence in this sample. This finding does not seem to be due solely to an association between suicide and alcohol dependence. There was more modest evidence of linkage to chromosomes 1 and 3 for suicidality; however, these findings did not reach statistical significance. There was no overlap in findings for these two phenotypes of suicidal behavior.

Alcoholism↗

PubMed2004

Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12q13.

Avascular necrosis of the femoral head (ANFH) is a debilitating disease that commonly leads to destruction of the hip joint in adults. The etiology of ANFH is unknown, but previous studies have indicated that heritable thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH. We recently identified two families with ANFH showing autosomal dominant inheritance. By applying linkage analysis to a four-generation pedigree, we excluded linkage between the family and three genes related to thrombophilia and hypofibrinolysis: protein C, protein S, and plasminogen activator inhibitor. Furthermore, by a genomewide scan, a significant two-point LOD score of 3.45 (recombination fraction [theta] = 0) was obtained between the family with ANFH and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second family with ANFH and replicated the linkage to D12S368 (pedigree I: LOD score 2.47, theta = 0.05; pedigree II: LOD score 2.81, theta = 0.10). When an age-dependent-penetrance model was applied, the combined multipoint LOD score was 6.43 between D12S1663 and D12S85. Thus, we mapped the candidate gene for autosomal dominant ANFH to a 15-cM region between D12S1663 and D12S1632 on chromosome 12q13.

Adolescent↗