The structures of the human neuronal nicotinic acetylcholine receptor β2- and α3-subunit genes (CHRNB2 and CHRNA3)

The α4-subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR) subunit family has recently been identified in two families as the gene responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare monogenic idiopathic epilepsy. As a result of this finding, other subunits of the neuronal nAChR gene family are being considered as candidate genes for ADNFLE in families not linked to CHRNA4 and for other idiopathic epilepsies. α4-subunitsoften assemble together with β2-subunits (gene symbol CHRNB2) to build heteromeric nAChRs. The gene encoding another abundant AChR subunit, the α3-subunit gene (CHRNA3), is present with those encoding two other subunits, CHRNB4 and CHRNA5, in a gene cluster whose functional role is still unclear. Here we provide the information on the genomic structures of both the CHRNB2 and the CHRNA3 genes that is necessary for comprehensive mutational analyses, and we refine the genomic assignment of CHRNB2 on chromosome 1. Received: 5 August 1998 / Accepted: 13 October 1998     

Search for alpha4 and alpha7 nicotinic acetylcholine receptor markers in a pedigree of benign familial infantile convulsions (BFIC)

In this study we investigate the possible involvement of the recently reported locus for benign familial infantile convulsions (BFIC) in human chromosome 19 and that of the neuronal acetylcholine receptor 4 (CHRNA4) and 7 (CHRNA7) subunits in a family with at least twelve clinically diagnosed cases of BFIC. Six polymorphic microsatellite markers covering the BFIC locus on chromosomal region 19q, one marker for CHRNA4 (chromosome 20) and two for CHRNA7 (chromosome 15) were used for the screening. The two-point lod score analysis showed no evidence of BFIC phenotype on chromosome 19. Similarly, when markers for chromosome 20 (CHRNA4 intron1, Amplimer: CHRNA4. PCR.1) and chromosome 15 (D15S165 and D15S1010) were used, score analysis showed no indication of linkage. The most likely interpretation of these results is that BFIC is a genetically heterogeneous form of epilepsy.     

Polymorphisms in the neural nicotinic acetylcholine receptor α4 subunit (CHRNA4) are associated with ADHD in a genetic isolate

The neural nicotinic acetylcholine receptor α4 subunit (CHRNA4), at 20q13.2-q13.3, is an important candidate gene for conferring susceptibility to attention deficit/hyperactivity disorder (ADHD). Several studies have already looked for association/linkage between ADHD and CHRNA4 in different populations. We used the Pedigree Disequilibrium Test to search for evidence of association between ADHD and six SNP marker loci in families from the isolated Paisa population. We found that the T allele of SNP rs6090384 exhibits a deficit of transmission in unaffected individuals (OR = 5.43, IC 1.54-19.13) (global P value = 0.014). We also found significant association and linkage to extended haplotypes rs2273502-rs6090384 (combination of variants C-T, respectively) (P = 0.02) and rs6090384-rs6090387 (P = 0.04) (combination of variants T-G, respectively). SNP rs6090384, variant T, has also been reported to be associated with inattention in a previous study. This makes ours the ninth study to examine the association of CHRNA4 with ADHD and the seventh one to find evidence for association in a population with a different ethnicity.     

Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) can be caused by mutations in the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4 and CHRNB2. Recently, a point mutation (α2-I279N) associated with sleep-related epilepsy has been described in a third nAChR gene, CHRNA2. We demonstrate here that α2-I279N can be co-expressed with the major structural subunit CHRNB2. α2-I279N causes a marked gain-of-function effect and displays a distinct biopharmacological profile, including markedly reduced inhibition by carbamazepine and increased nicotine sensitivity.     

Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by both population and phenotypic heterogeneity. Our group previously identified linkage to SLE at 4p16 in European Americans (EA). In the present study we replicate this linkage effect in a new cohort of 76 EA families multiplex for SLE by model-free linkage analysis. Using densely spaced microsatellite markers in the linkage region, we have localized the potential SLE susceptibility gene(s) to be telomeric to the marker D4S2928 by haplotype construction. In addition, marker D4S394 showed marginal evidence of linkage disequilibrium with the putative disease locus by the transmission disequilibrium test and significant evidence of association using a family-based association approach as implemented in the program ASSOC. We also performed both two-point and multipoint model-based analyses to characterize the genetic model of the potential SLE susceptibility gene(s), and the lod scores both maximized under a recessive model with penetrances of 0.8. Finally, we performed a genome-wide scan of the total 153 EA pedigrees and evaluated the possibility of interaction between linkage signals at 4p16 and other regions in the genome. Fourteen regions on 11 chromosomes (1q24, 1q42, 2p11, 2q32, 3p14.2, 4p16, 5p15, 7p21, 8p22, 10q22, 12p11, 12q24, 14q12, 19q13) showed evidence of linkage, among which, signals at 2p11, 12q24 and 19q13 also showed evidence of interaction with that at 4p16. These results provide important additional information about the SLE linkage effect at 4p16 and offer a unique approach to uncovering susceptibility loci involved in complex human diseases.     

Characterization of allelic variants at chromosome 15q14 in schizophrenia

Evidence of genetic linkage for schizophrenia at chromosome 15q14 has been reported in nine independent studies, but the molecular variants responsible for transmission of genetic risk are unknown. National Institute of Mental Health Schizophrenia Genetics Initiative families were genotyped for single nucleotide polymorphisms (SNPs) and dinucleotide repeat markers in the 15q14 linkage region and analyzed based on the presence of particular alleles of the dinucleotide repeat marker D15S165 in the 15q14 region. Two alleles showed both familial transmission disequilibrium and population-wide association with schizophrenia. The two groups identified by these two D15S165 alleles differ in age of onset, number of hospitalizations and intensity of nicotine abuse, as well as in predominant ethnicity. Variations in the frequency of SNPs in CHRNA7 , the α-7-nicotinic acetylcholine receptor subunit gene at 15q14, were found in each group. Further sequencing in these two groups may yield more definitive identification of the molecular pathology.     

Genomewide Linkage Analysis of Celiac Disease in Finnish Families

Celiac disease (CD), or gluten-sensitive enteropathy, is a common multifactorial disorder resulting from intolerance to cereal prolamins. The only established genetic susceptibility factor is HLA-DQ, which appears to explain only part of the overall genetic risk. We performed a genomewide scan of CD in 60 Finnish families. In addition to strong evidence for linkage to the HLA region at 6p21.3 (Z(max)>5), suggestive evidence for linkage was found for six other chromosomal regions--1p36, 4p15, 5q31, 7q21, 9p21-23, and 16q12. We further analyzed the three most convincing regions--4p15, 5q31, and 7q21--by evaluation of dense marker arrays across each region and by analysis of an additional 38 families. Although multipoint analysis with dense markers provided supportive evidence (multipoint LOD scores 3.25 at 4p15, 1.49 at 5q31, and 1.04 at 7q21) for the initial findings, the additional 38 families did not strengthen evidence for linkage. The role that HLA-DQ plays was studied in more detail by analysis of DQB1 alleles in all 98 families. All but one patient carried one or two HLA-DQ risk alleles, and 65% of HLA-DQ2 carriers were affected. Our study indicates that the HLA region harbors a predominant CD-susceptibility locus in these Finnish families.     

Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24

We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.     

Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear

Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.     

Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

To examine the genetic basis of age-related macular degeneration (ARMD), a degenerative disease of the retinal pigment epithelium and neurosensory retina, we conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy. Family and medical history was obtained from index cases and family members. Fundus photographs were taken of all participating family members, and these were graded for severity by use of a quantitative scale. Model-free linkage analysis was performed, and tests of heterogeneity and epistasis were conducted. We have evidence of a major locus on chromosome 15q (GATA50C03 multipoint P=1.98x10-7; empirical P< or =1.0x10-5; single-point P=3.6x10-7). This locus was present as a weak linkage signal in our previous genome scan for ARMD, in the Beaver Dam Eye Study sample (D15S659, multipoint P=.047), but is otherwise novel. In this genome scan, we observed a total of 13 regions on 11 chromosomes (1q31, 2p21, 4p16, 5q34, 9p24, 9q31, 10q26, 12q13, 12q23, 15q21, 16p12, 18p11, and 20q13), with a nominal multipoint significance level of P< or =.01 or LOD > or =1.18. Family-by-family analysis of the data, performed using model-free linkage methods, suggests that there is evidence of heterogeneity in these families. For example, a single family (family 460) individually shows linkage evidence at 8 loci, at the level of P<.0001. We conducted tests for heterogeneity, which suggest that ARMD susceptibility loci on chromosomes 9p24, 10q26, and 15q21 are not present in all families. We tested for mutations in linked families and examined SNPs in two candidate genes, hemicentin-1 and EFEMP1, in subsamples (145 and 189 sib pairs, respectively) of the data. Mutations were not observed in any of the 11 exons of EFEMP1 nor in exon 104 of hemicentin-1. The SNP analysis for hemicentin-1 on 1q31 suggests that variants within or in very close proximity to this gene cause ARMD pathogenesis. In summary, we have evidence for a major ARMD locus on 15q21, which, coupled with numerous other loci segregating in these families, suggests complex oligogenic patterns of inheritance for ARMD.     

Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci

Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome‐wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow‐up in an additional 21 families at linked loci. We used two‐point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12‐22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1‐23.2, centering over the FHM2 locus (two‐point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine‐affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12‐22, and a second locus that may contribute to migraine in the general population at 1q23.1‐23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine‐mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy‐associated migraine.     

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.     

Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families

Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeostasis that results from the autoimmune destruction of the insulin-secreting cells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparently conflicting results, despite partial overlap in the families analyzed. However, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda(s)) <1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these genome scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with lambda(s) = 1.3 at P=7.4x10(-4). Three chromosome regions were identified that showed significant evidence of linkage (P<2.2x10(-5); LOD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22-q24, and four more that showed suggestive evidence (P<7.4x10(-4), LOD scores > or =2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15), and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes, and the results point to the value of future international collaborations to assemble and analyze much larger data sets for linkage in complex diseases.     

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD?=?4.51, α?=?0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD?=?3.60, α?=?0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD?=?3.07, α?=?0.29; dominant HLOD?=?3.03, α?=?0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD?=?3.02, α?=?0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.     

Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.     

Benign familial neonatal convulsions: confirmation of genetic heterogeneity and further evidence for a second locus on chromosome 8q

The syndrome of benign familial neonatal convulsions (BFNC) is a rare, autosomal dominant form of epilepsy. It is characterized by spontanous seizures beginning within the first 6 months of life. In the majority of families linkage is to chromosome 20q markers. Based on the linkage results in one large BFNC kindred, genetic heterogeneity and existence of a second locus on chromosome 8 have been suggested. Here we report on a second BFNC family in which linkage to the EBN1 locus on chromosome 20q was excluded, confirming the genetic heterogeneity of this disorder. All affected family members experienced onset of seizures before the age of 2 months. Three BFNC subjects showed subsequent epileptic seizures after 12 months of age, showing that the risk of subsequent epilepsy is not restricted to the chromosome 20q linked BFNC families. A lod score of 0.99 was obtained with the marker D8S274, suggesting linkage to chromosome 8.     

A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3

Hot water epilepsy (HWE) is a form of reflex or sensory epilepsy wherein seizures are precipitated by an unusual stimulus, the contact of hot water over the head and body. Genome-wide linkage analysis of a large family with ten affected members, provided evidence of linkage (Z _max = 3.17 at θ = 0 for D10S412) to chromosome 10q21. Analysis of five additional HWE families, for markers on chromosome 10, further strengthened the evidence of linkage to the same chromosomal region with three out of five families showing concordance for the disease haplotype and providing a two-point LOD score of 4.86 at θ = 0 and 60% penetrance for D10S412. The centromere-proximal and -distal boundaries of the critical genetic interval of about 15 Mb at 10q21.3-q22.3 were defined by D10S581 and D10S201, respectively. Sequence analysis of a group of functional candidate genes, the ion channels KCNMA1, VDAC2 and solute carriers SLC25A16, SLC29A3 revealed no potentially pathogenic mutation. We propose to carry out further analysis of positional candidate genes from this region to identify the gene responsible for this unusual neurobehavioral phenotype.     

The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q

We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.63 on 6q; P<.0001 and P=.0001, respectively, after a genomewide permutation procedure). The second-best BPAD interaction evidence was observed between chromosomes 2q22-q24 and 15q26. Here, we also observed a symmetrical interaction (NPL scores of 6.26 on 2q and 4.59 on 15q; P=.0057 and .0022, respectively). We covered the implicated regions by genotyping additional marker sets and performed a detailed interaction linkage analysis, which narrowed the susceptibility intervals. Although the heterogeneity analysis produced less impressive results (highest NPL score of 3.32) and a less consistent picture, we achieved evidence of locus heterogeneity at chromosomes 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. Our results provide systematic insights in the framework of BPAD epistasis and locus heterogeneity, which should facilitate gene identification by the use of more-comprehensive cloning strategies.     

Evidence for the localization of a malignant hyperthermia susceptibility locus (MHS2) to human chromosome 17q.

Malignant hyperthermia susceptibility is a lethal autosomal dominant disorder of skeletal muscle metabolism that is triggered by all potent inhalation anesthetic gases. Recent linkage studies suggest a genetic locus for this disorder on 19q13.1. We have previously reported three unrelated families diagnosed with MHS that are unlinked to markers surrounding this locus on 19q13.1. In this report we extend these observations and present linkage studies on 16 MHS families. Four families (25%) were found linked to the region 19q12-q13.2 (Zmax = 2.96 with the ryanodine receptor at theta = 0.0). Five families (31%) were found closely linked to the anonymous marker NME1 (previously designated NM23) on chromosome 17q11.2-q24 (Zmax = 3.26 at theta = 0.0). Two families (13%) were clearly unlinked to either of these chromosomal regions. In five additional families, data were insufficient to determine their linkage status (they were potentially linked to two or more sites). The results of our heterogeneity analyses are consistent with the hypothesis that MHS can be caused in humans by any one of at least three distinct genetic loci. Furthermore, we provide preliminary linkage data suggesting the localization of a gene in human MHS to 17q11.2-q24 (MHS2), with a gene frequency of this putative locus approximately equal to that of the MHS1 locus on 19q.     

A genomewide scan identifies novel early-onset primary open-angle glaucoma loci on 9q22 and 20p12

Glaucoma is a leading cause of blindness worldwide. The disease is characterized by a degeneration of the optic nerve, which is usually associated with elevated intraocular pressure. The common form of adult-onset primary open-angle glaucoma is inherited as a complex trait, whereas the rarer early-onset juvenile open-angle glaucoma (JOAG) exhibits autosomal dominant inheritance. Of all cases of JOAG, approximately 10%-20% are caused by mutations in the myocilin gene. We have identified 25 pedigrees that are affected with typical JOAG and that demonstrate autosomal dominant inheritance. We sequenced the myocilin gene in probands from each family and found mutations in 8% of this population. To identify novel genes responsible for JOAG, we used families that did not have myocilin mutations for a genomewide screen. Markers located on chromosomes 9q22 and 20p12 showed evidence for linkage, identifying two novel loci for early-onset open-angle glaucoma.