Migraine with Aura Susceptibility Locus on Chromosome 19p13 Is Distinct from the Familial Hemiplegic Migraine Locus

Migraine is a common neurological disease with a major genetic component. Recently, it has been proposed that a single locus on chromosome 19p13 contributes to the genetic susceptibility of both rare familial hemiplegic migraine (FHM) and more common types of migraine, migraine with aura and migraine without aura. We analyzed 16 families for co-segregation of migraine with aura and chromosome 19p13 markers. Using multipoint model-free linkage analysis, we obtained a lod score of 4.28 near D19S592. Using an affecteds-only model of linkage, we observed a lod score of 4.79 near D19S592. We were able to provide statistical evidence that this locus on chromosome 19p13 is most likely not the gene CACNA1A, mutations in which cause FHM. These data indicate that chromosome 19p13 contains a locus which contributes to the genetic susceptibility of migraine with aura that is distinct from the FHM locus.     

Genetic dissection of gustatory sensitivity to bitterness (sucrose octaacetate) in mice

Genes implicated in consumption of a bitter compound, sucrose octaacetate (SOA), were investigated using a full genomic scanning strategy. For a 0.1 mM concentration, two QTL reached 5.8 and 6.5 lod scores on chromosomes 2 (77 cM) and 11 (14 cM), respectively. For a 1 mM concentration, the Soa linkage on chromosome 6 (58 cM, lod score 9.4) was replicated, and another QTL was found on chromosome 19 (15 cM, lod score 3.2). Candidacy of previously identified genes in the close vicinity of the peak of the QTL was examined.     

Linkage of hereditary motor and sensory neuropathy type I to the pericentromeric region of chromosome 17.

Vance et al. have reported linkage of hereditary motor and sensory neuropathy type I (HMSN I) to the pericentromeric region of chromosome 17. We have studied eight families with HMSN I (also called the hypertrophic form of Charcot-Marie-Tooth disease) for linkage of the disease locus to polymorphic loci in the centromeric region of chromosome 17. Linkage has been confirmed for D17S58 (EW301) with a maximum lod score of 5.89 at theta = 0.08 and for D17S71 (pA10-41) with a maximum lod score of 3.22 at theta = 0.08. EW301 is on 17p, 5.5 centimorgans from the centromere. Two families, previously reported as being linked to the Duffy blood group locus on chromosome 1, were included in this study, and one now provides positive lod scores for chromosome 17 markers. There was no evidence of heterogeneity.     

Linkage of prostate cancer susceptibility loci to chromosome 1

Three prostate cancer susceptibility genes have been reported to be linked to different regions on chromosome 1: HPC1 at 1q24-25, PCAP at 1q42-43, and CAPB at 1p36. Replication studies analyzing each of these regions have yielded inconsistent results. To evaluate linkage across this chromosome systematically, we performed multipoint linkage analyses with 50 microsatellite markers spanning chromosome 1 in 159 hereditary prostate cancer families (HPC), including 79 families analyzed in the original report describing HPC1 linkage. The highest lod scores for the complete dataset of 159 families were observed at 1q24-25 at which the parametric lod score assuming heterogeneity (hlod) was 2.54 (P=0.0006) with an allele sharing lod of 2.34 (P=0.001) at marker D1S413, although only weak evidence was observed in the 80 families not previously analyzed for this region (hlod=0.44, P=0.14, and allele sharing lod=0.67, P=0.08). In the complete data set, the evidence for linkage across this region was very broad, with allele sharing lod scores greater than 0.5 extending approximately 100 cM from 1p13 to 1q32, possibly indicating the presence of multiple susceptibility genes. Elsewhere on chromosome 1, some evidence of linkage was observed at 1q42-43, with a peak allele sharing lod of 0.56 (P=0.11) and hlod of 0.24 (P=0.25) at D1S235. For analysis of the CAPB locus at 1p36, we focused on six HPC families in our collection with a history of primary brain cancer; four of these families had positive linkage results at 1p36, with a peak allele sharing lod of 0.61 (P=0.09) and hlod of 0.39 (P=0.16) at D1S407 in all six families. These results are consistent with the heterogeneous nature of hereditary prostate cancer, and the existence of multiple loci on chromosome 1 for this disease.     

Multiple QTLs influence variation in paraoxonase 1 activity in Mexican Americans

Paraoxonase 1 (PON1), a high-density-lipoprotein-associated enzyme known to protect against cellular damage from toxic agents, may also have antioxidant properties. Although the importance of the influence of the PON1 structural locus on chromosome 7q21-22 for variation in the concentration and activity of the enzyme is well-documented, the contribution of other loci is poorly understood. Based on the recent observations of at least one additional quantitative trait locus (QTL) for PON1 activity in pedigreed baboons, we conducted a whole-genome linkage screen for QTLs other than the PON1 structural locus that may influence PON1 activity in humans. We measured PON1 activity in frozen serum for 1,406 individuals in more than 40 extended pedigrees from the San Antonio Family Heart Study (SAFHS). We used a maximum-likelihood-based variance decomposition approach implemented in SOLAR to test for QTLs that may influence PON1 activity. In addition to a QTL for which we detected the strongest, significant evidence (LOD = 31.41) at or near the PON1 structural locus on chromosome 7q21-22, we also localized at least one additional significant QTL on chromosome 12 (LOD = 3.56). Furthermore, we detected suggestive evidence for two more PON-related QTLs on chromosomes 17 and 19. We have provided evidence that other genes, in addition to the well-known ones on chromosome 7, play a role in influencing normal variation in PON1 activity.     

Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity.

We examined the relationship between cutaneous malignant melanoma/dysplastic nevi (CMM/DN) and chromosome 9p in 13 pedigrees with two or more living cases of invasive melanoma. We used two highly informative (CA)n repeats, D9S126 and IFNA, previously implicated in familial malignant melanoma (MLM), to conduct linkage analysis. Three analyses were performed: (1) CMM alone--all individuals without either confirmed melanoma or borderline lesions were considered unaffected (model A); (2) CMM/DN with both variable age at onset and sporadics (model B); and (3) CMM affecteds only--all individuals either without confirmed melanoma or with borderline lesions were designated "unknown" (model C). There was significant evidence for linkage to IFNA in all three models. For CMM alone, the maximum lod score (Zmax) was 4.36 at theta = .10 for model A and 3.39 at theta = .10 for model C. For CMM/DN (model B), Zmax = 3.05 at theta = .20. There was no significant evidence for linkage between CMM alone or CMM/DN and chromosome 9p marker D9S126. In addition, there was significant evidence for heterogeneity when a homogeneity test allowing for linkage to chromosome 9p or chromosome 1p or neither region was used. These results suggest that there is an MLM susceptibility locus on chromosome 9p but that familial melanoma is heterogeneous and not all families with CMM/DN are linked to a locus in this region.     

Recombination between rhodopsin and locus D3S47 (C17) in rhodopsin retinitis pigmentosa families

Autosomal dominant retinitis pigmentosa (adRP) has shown linkage to the chromosome 3q marker C17 (D3S47) in two large adRP pedigrees known as TCDM1 and adRP3. On the basis of this evidence the rhodopsin gene, which also maps to 3q, was screened for mutations which segregated with the disease in adRP patients, and several have now been identified. However, we report that, as yet, no rhodopsin mutation has been found in the families first linked to C17. Since no highly informative marker system is available in the rhodopsin gene, it has not been possible to measure the genetic distance between rhodopsin and D3S47 accurately. We now present a linkage analysis between D3S47 and the rhodopsin locus (RHO) in five proven rhodopsin-retinitis pigmentosa (rhodopsin-RP) families, using the causative mutations as highly informative polymorphic markers. The distance, between RHO and D3S47, obtained by this analysis is theta = .12, with a lod score of 4.5. This contrast with peak lod scores between D3S47 and adRP of 6.1 at theta = .05 and 16.5 at theta = 0 in families adRP3 and TCDM1, respectively. These data would be consistent with the hypothesis that TCDM1 and ADRP3 represent a second adRP locus on chromosome 3q, closer to D3S47 than is the rhodopsin locus. This result shows that care must be taken when interpreting adRP exclusion data generated with probe C17 and that it is probably not a suitable marker for predictive genetic testing in all chromosome 3q-linked adRP families.     

Fanconi anemia: evidence for linkage heterogeneity on chromosome 20q

Fanconi anemia is a rare autosomal recessive disorder in which affected individuals are predisposed to acute myelogenous leukemia and other malignancies. We report the results of a genetic linkage study involving 34 families enrolled in the International Fanconi Anemia Registry. A significant lod score was obtained between D20S20, an anonymous DNA segment from chromosome 20q, and Fanconi anemia (Zmax 3.04, theta max = 0.12). However, six other anonymous DNA segments from chromosome 20q, including D20S19, which is highly polymorphic and tightly linked to D20S20, showed no or only weak evidence for linkage to Fanconi anemia. An admixture test revealed significant evidence for linkage heterogeneity (chi 2 = 6.10, P = 0.01) at the D20S19 locus. Lod scores suggestive of linkage between Fanconi anemia and this locus were obtained with two of the largest kindreds studied (lods = 2.6 and 2.1, at theta = 0.001). Thus, our data support the provisional assignment of a Fanconi anemia gene to chromosome 20q.     

Genetic heterogeneity in X-linked amelogenesis imperfecta.

The AMELX gene located at Xp22.1-p22.3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.05 for DXS16 at theta = 0.04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multipoint linkage analysis, the combined maximum lod score for these two families was 7.30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2.84 at theta = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9.(ABSTRACT TRUNCATED AT 250 WORDS)     

Linkage analysis of the apolipoprotein C2 gene and myotonic dystrophy on human chromosome 19 reveals linkage disequilibrium in a French-Canadian population.

The gene for human apolipoprotein C2 (APOC2), situated on the proximal long arm of chromosome 19, is closely linked to the gene for the most common form of adult muscular dystrophy, myotonic dystrophy (DM). Six APOC2 RFLPs (TaqI, BglI, BanI, BamHI, NcoI, and AvaII) have been identified to date. We have conducted a comprehensive DM linkage study utilizing all six RFLPs and involving 50 families and 372 individuals. The most informative RFLPs are, in descending order, NcoI (lod = 6.64, theta = 0.05), BglI (lod = 6.12, theta = 0.05), AvaII (lod = 6.02, theta = 0.03), BanI (lod = 5.76, theta = 0.04), TaqI (lod = 4.29, theta = 0.06), and BamHI (lod = 1.75, theta = 0.01). A substantial increase in the lod scores over those seen with the individual RFLPs was obtained when the linkage of the entire APOC2 haplotype (composed of the six RFLPs) was studied (lod = 17.87, theta = 0.04). We have observed significant inter-APOC2 RFLP linkage disequilibrium. Consequently, the three most informative RFLPs have been found to be BanI, TaqI, and either BglI, AvaII, or NcoI polymorphisms. We also demonstrate linkage disequilibrium between DM and APOC2 in our French-Canadian population (standardized disequilibrium constant phi = .22, chi 2 = 5.12, df = 1, P less than 0.04). This represents the first evidence of linkage disequilibrium between APOC2 and the DM locus.     

Relationship of growth hormone and insulin-like growth factor-1 genotypes with growth and carcass traits in swine

The contribution of chromosomal regions linked to growth hormone (GH) and insulin-like growth factor-1 (IGF-1) loci to variation in preweaning average daily gain, postweaning average daily gain (ADG), 10th rib backfat, loin-eye area and muscle pH were evaluated. Offspring of four purebred sires (A–D; n = 150, 195, 148 and 136, respectively) and two crossbred sires (E and F; n = 157 and 145, respectively) were genotyped initially with GH and IGF-1 markers. When results of single marker analysis suggested possible linkage with a quantitative trait locus (QTL), additional flanking markers were typed for the family and interval mapping was performed. Growth hormone genotype was not associated with the traits evaluated in the study. Evidence suggestive of linkage was found for IGF-1 genotype and ADG in one sire family (lod = 2·3) where differences were 0.032 ± 0·01 kg/day for alternative sire alleles. Evidence for a putative ADG QTL was greatest in the interval between IGF-1 and Sw1071. A similar genomic region has been associated with growth variation in mice; however, QTL mapping precision in the current study is insufficient to establish similarity.     

A genome scan for Loci associated with aerobic running capacity in rats

Aerobic capacity is a complex trait that defines the efficiency to use atmospheric oxygen as an electron acceptor in energy transfer. Copenhagen (COP) and DA inbred rat strains show a wide difference in a test for aerobic treadmill running and serve as contrasting genetic models for aerobic capacity. A genome scan was carried out on an F(2)(COP x DA) segregating population (n=224) to detect quantitative trait loci (QTLs) associated with aerobic running capacity. Linkage analysis revealed a significant QTL on chromosome 16 (lod score, 4.0). A suggestive linkage was found near the p-terminus of chromosome 3 (lod score, 2.2) with evidence of an interaction with another QTL on chromosome 16 (lod score, 2.9). All three QTLs showed a dominant mode of inheritance in which the presence of at least one DA allele was associated with a greater distance run. These results represent the first aerobic capacity QTLs identified in genetic models.     

Multiple Genes Influence BMI on Chromosome 7q31–34: The NHLBI Family Heart Study

The National Heart, Lung, and Blood Institute Family Heart Study (FHS) genome‐wide linkage scan identified a region of chromosome 7q31–34 with a lod score of 4.9 for BMI at D7S1804 (131.9 Mb). We report the results of linkage and association to BMI in this region for two independent FHS samples. The first sample includes 225 FHS pedigrees with evidence of linkage to 7q31–34, using 1,132 single‐nucleotide polymorphisms (SNPs) and 7 microsatellites. The second represents a case–control sample (318 cases; BMI >25 and 325 controls; BMI <25) derived from unrelated FHS participants who were not part of the genome scan. The latter set was genotyped for 606 SNPs, including 37 SNPs with prior evidence for association in the linked families. Although variance components linkage analysis using only SNPs generated a peak lod score that coincided with the original linkage scan at 131.9 Mb, a conditional linkage analysis showed evidence of a second quantitative trait locus (QTL) near 143 cM influencing BMI. Three SNPs (rs161339, rs12673281, and rs1993068) located near the three genes pleiotrophin (PTN), diacylglycerol (DAG) kinase iota (DGKι), and cholinergic receptor, muscarinic 2 (CHRM2) demonstrated significant association in both linked families (P = 0.0005, 0.002, and 0.03, respectively) and the case–control sample (P = 0.01, 0.0003, and 0.03, respectively), regardless of the genetic model tested. These findings suggest that several genes may be associated with BMI in the 7q31–34 region.     

Genetic analysis of a complex trait in the Utah Genetic Reference Project: a major locus for PTC taste ability on chromosome 7q and a secondary locus on chromosome 16p

The ability to taste phenylthiocarbamide (PTC) shows complex inheritance in humans. We obtained a quantitative measure of PTC tasting ability in 267 members of 26 large three-generation families that were part of a set of CEPH families that had been used for genetic mapping. Significant bimodality was found for the distribution of age and gender adjusted scores (P<0.001), with estimated means of 3.16 (SD=1.80) and 9.26 (SD=1.54). Using the extensive genotyping available in these families from the genetic mapping efforts, we performed a genome scan by using 1324 markers with an average spacing of 4 cM. Analyses were first carried out with a recessive genetic model that has traditionally been assumed for the trait, and a threshold score of 8.0 delineating tasters from non-tasters. In this qualitative analysis, the maximum genome-wide lod score was 4.74 at 246 cM on chromosome 7; 17 families showed segregation of the dichotomous PTC phenotype. No other lod scores were significant; the next highest score was on chromosome 10 (lod=1.64 at 85 cM), followed by chromosome 3 (lod=1.29 at 267 cM). Because PTC taste ability exhibited substantial quantitative variation, the quantitative trait was also analyzed by using a variance components approach in SOLAR. The maximum quantitative genome-wide lod score was 8.85 at 246 cM on chromosome 7. Evidence for other possible quantitative loci was found on chromosomes 1 (lod=2.31 at 344 cM) and 16 (lod=2.01 at 14 cM). A subsequent two-locus whole-genome scan conditional on the chromosome 7 quantitative trait locus identified the chromosome 16 locus (two-locus lod=3.33 at 14 cM).     

Linkage between the loci for the Lp(a) lipoprotein (LP) and plasminogen (PLG)

Summary A locus, LP, that determines quantitative variation of Lp(a) lipoprotein phenotypes is linked to the plasminogen (PLG) locus (peak lod score =12.73). This linkage relationship assigns a locus with alleles that have an affect on risk for coronary artery disease to the long arm of chromosome 6.     

Pleiotropic QTL on chromosome 12q23-q24 influences triglyceride and high-density lipoprotein cholesterol levels: the HERITAGE family study

To determine whether a common quantitative trait locus (QTL) influences the variation of fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, we used a bivariate multipoint linkage analysis with 654 polymorphic markers in 99 white and 101 black families. The phenotypes were investigated under two conditions: at baseline and after a 20-week exercise training intervention. A maximum genome-wide bivariate LOD score of 3.0 (p = 0.00010) was found on chromosome 12q23-q24, located within the IGF1 gene (insulin-like growth factor 1, at 107 cM) for TG and HDL-C at baseline in whites. This bivariate linkage peak is considerably higher than the univariate linkage results at the same chromosome location for either trait (for TG, LOD = 2.07, p = 0.00108; for HDL-C, LOD = 2.04, p = 0.00101). The genetic correlations between baseline TG and HDL-C levels were -0.14 for the residual and -0.33 for the QTL components. Moreover, association analysis showed that TG, HDL-C, and IGF1 are significantly associated (p = 0.04). In conclusion, these results suggest that a QTL on chromosome 12q23-q24 influences the variation of plasma TG and HDL-C levels. Further investigation should confirm whether IGF1 or another nearby gene is responsible for the concomitant variation in TG and HDL-C levels.     

Does haplotype diversity predict power for association mapping of disease susceptibility?

Atopy is an IgE-mediated condition known to aggregate in families and is a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome-wide scan for atopy, defined by skin sensitivity to one or more common environmental allergens, was conducted in 287 CSGA families (115 African American, 138 Caucasian and 34 Hispanic). Using a nonparametric genetic analysis approach, two regions were observed in the sample of all families that yielded multipoint lod scores >1.5 (chromosome 11q, lod=1.55 between D11S1986 and D11S1998; chromosome 20p between D20S473 and D20S604, lod=1.54). Modeling that included multiple genomic positions simultaneously indicated that four chromosomal regions accounted for the majority of evidence for linkage in the combined families. These four regions are on chromosomes 10p near D10S1412 (lod=0.94), 11q near D11S1986 (lod=1.76), 17q near D17S784 (lod=0.97) and 20p near D20S473 (lod=1.74). In the subset of pedigrees giving positive evidence for linkage on chromosome 11q, the evidence for linkage increased by lod scores greater than one in four other chromosomal regions: 5q (D5S1480, lod=1.65), 8p (D8S1113, lod=1.60), 12p (D12S372, lod=1.54) and 14q (D14S749, lod=1.70). These results suggest that several regions may harbor genes contributing to the risk for atopy and these may interact with one another in a complex manner.This work is published on behalf of the NHLBI Collaborative Study on the Genetics of Asthma     

Autosomal dominant familial spastic paraplegia: tight linkage to chromosome 15q.

Autosomal dominant, uncomplicated familial spastic paraplegia (FSP) is a genetically heterogeneous disorder characterized by insidiously progressive lower-extremity spasticity. Recently, a locus on chromosome 14q was shown to be tightly linked with the disorder in one of three families. We performed linkage analysis in a kindred with autosomal dominant uncomplicated FSP. After excluding the chromosome 14q locus, we observed tight linkage of the disorder to a group of markers on chromosome 15q (maximum two-point lod score 9.70; theta = .05). Our results clearly establish the existence of a locus for autosomal dominant FSP in the centromeric region of chromosome 15q. Comparing clinical and genetic features in FSP families linked to chromosome 14q with those linked to chromosome 15q may provide insight into the pathophysiology of this disorder.     

Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus

We have previously reported linkage of systemic lupus erythematosus to chromosome 2q37 in multicase families from Iceland and Sweden. This locus (SLEB2) was identified by linkage to the markers D2S125 and D2S140. In the present study we have analyzed additional microsatellite markers and SNPs covering a region of 30 cM around D2S125 in an extended set of Nordic families (Icelandic, Swedish, and Norwegian). Two-point linkage analysis in these families gave a maximum lod score at the position of markers D2S2585 and D2S2985 (Z = 4.51, PIC = 0.65), by applying a "model-free" pseudo-marker linkage analysis. Based on multipoint linkage analysis in the Nordic families, the most likely location of the SLEB2 locus is estimated to be in the interval between D2S125 and the position of markers D2S2585 and D2S2985, with a peak multipoint lod score of Z = 6.03, assuming a dominant pseudo-marker model. Linkage disequilibrium (LD) analysis was performed using the data from the multicase families and 89 single-case families of Swedish origin, using the same set of markers. The LD analysis showed evidence for association in the single-case and multicase families with locus GAAT3C11 (P < 0.0003), and weak evidence for association was obtained for several markers located telomeric to D2S125 in the multicase families. Thirteen Mexican families were analyzed separately and found not to have linkage to this region. Our results support the presence of the SLEB2 locus at 2q37.     

A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q.

We have rated eye color on a 3-point scale (1 = blue/grey, 2 = hazel/green, 3 = brown) in 502 twin families and carried out a 5-10 cM genome scan (400-757 markers). We analyzed eye color as a threshold trait and performed multipoint sib pair linkage analysis using variance components analysis in Mx. A lod of 19.2 was found at the marker D15S1002, less than 1 cM from OCA2, which has been previously implicated in eye color variation. We estimate that 74% of variance in eye color liability is due to this QTL and a further 18% due to polygenic effects. However, a large shoulder on this peak suggests that other loci affecting eye color may be telomeric of OCA2 and inflating the QTL estimate. No other peaks reached genome-wide significance, although lods > 2 were seen on 5p and 14q and lods >1 were additionally seen on chromosomes 2, 3, 6, 7, 8, 9, 17 and 18. Most of these secondary peaks were reduced or eliminated when we repeated the scan as a two locus analysis with the 15q linkage included, although this does not necessarily exclude them as false positives. We also estimated the interaction between the 15q QTL and the other marker locus but there was only minor evidence for additive x additive epistasis. Elaborating the analysis to the full two-locus model including non-additive main effects and interactions did not strengthen the evidence for epistasis. We conclude that most variation in eye color in Europeans is due to polymorphism in OCA2 but that there may be modifiers at several other loci.