A typical migraine susceptibility region localizes to chromosome 1q31

Migraine (with and without aura) is a prevalent neurovascular disease that shows strong familial aggregation, although the number of genes involved and the mode of inheritance is not clear. Some insight into the disease has been gained from genetic studies into a rare and very severe migraine subtype known as familial hemiplegic migraine (FHM). In this study, we took a family-based linkage and association approach to investigate the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chr1q31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned approximately 18 cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782 (P=0.00004). Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P=0.008). Utilising the independent sample of 82 pedigrees, we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 [global χ² ₍₅₎ of 15.00, P=0.010] in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers. However, overall they provide good evidence for the existence of a typical migraine locus near these markers on Chr1q31, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. Electronic Publication     

X-chromosome markers and manic-depressive illness. Rejection of linkage to Xq28 in nine bipolar pedigrees

Numerous reports have been published concerning linkage of X-chromosome markers of the q28 region (including protan and deutan color blindness [CB] and glucose-6-phosphate dehydrogenase deficiency) to manic-depressive illness. We studied nine bipolar pedigrees (in which there was no male-to-male transmission) in an attempt to detect linkage, using three tightly linked polymorphic DNA loci, DXS15, DXS52 and F8C (factor 8 gene), all of which are closely linked to the CB and glucose 6-phosphate dehydrogenase classic Xq28 markers. Linkage to this region of Xq28 could be excluded unequivocally in these nine families. When these data were combined with our earlier series of bipolar pedigrees, informative for either protan or deutan CB, a total of 14 bipolar pedigrees have been studied, with no evidence of linkage or heterogeneity. At a recombination fraction (theta) of 1%, this series had greater than 95% power to detect linkage if only 50% of the pedigrees studied were linked to the CB region. Our failure to confirm the previously reported linkage of manic-depressive illness to the CB region of the X chromosome indicates that this linkage is not as common as previously suggested.     

The gene for X-linked myotubular myopathy is located in an 8 Mb region at the border of Xq27.3 and Xq28

X-linked recessive myotubular myopathy (XLMTM) is a rare and severe neonatal neuromuscular disease characterized by muscle weakness, hypotonia, and respiratory problems. Here we report an extensive linkage analysis in two families with XLMTM. Using 18 markers in the Xq27-Xqter region we found a maximum two-point lod score of Z = 4.00 at Θ = 0.00 for the marker II-10 (DXS466). Three recombinations were detected between markers and the disease locus. At the distal side of Xq27.3 a recombination was present in between RNI (DXS369) and VK23b (DXS297), another in between VK23b (DXS297) and II-10 (DXS466), and at the proximal side of Xq28 a recombination in between U6.2 (DXS304) and Cpx67 (DXS134). Combining the results of both families we conclude that XLMTM is located in the 8 Mb (11 cM) region between VK23b (DXS297) and Cpx67 (DXS134).     

A genome-wide scan provides evidence for loci influencing a severe heritable form of common migraine

Migraine is a prevalent neurovascular disease with a significant genetic component. Linkage studies have so far identified migraine susceptibility loci on chromosomes 1, 4, 6, 11, 14, 19 and X. We performed a genome-wide scan of 92 Australian pedigrees phenotyped for migraine with and without aura and for a more heritable form of severe migraine. Multipoint non-parametric linkage analysis revealed suggestive linkage on chromosome 18p11 for the severe migraine phenotype (LOD*=2.32, P=0.0006) and chromosome 3q (LOD*=2.28, P=0.0006). Excess allele sharing was also observed at multiple different chromosomal regions, some of which overlap with, or are directly adjacent to, previously implicated migraine susceptibility regions. We have provided evidence for two loci involved in severe migraine susceptibility and conclude that dissection of the migraine phenotype may be helpful for identifying susceptibility genes that influence the more heritable clinical (symptom) profiles in affected pedigrees. Also, we concluded that the genetic aetiology of the common (International Headache Society) forms of the disease is probably comprised of a number of low to moderate effect susceptibility genes, perhaps acting synergistically, and this effect is not easily detected by traditional single-locus linkage analyses of large samples of affected pedigrees.     

Autism spectrum disorders associated with X chromosome markers in French-Canadian males

It is now well established that genetic factors play an important role in the pathogenesis of autism disorder and converging lines of evidence suggest the implication of the X chromosome. Using a sample of subjects diagnosed with autism spectrum disorders, exclusively composed of males from French-Canadian (FC) origin, we tested markers covering the entire X chromosome using a family-based association study. Our initial analysis revealed the presence of association at two loci: DXS6789 (P=0.026) and DXS8043 (P=0.0101). In a second step, we added support to the association at DXS8043 using additional markers, additional subjects and a haplotype-based analysis (best obtained P-value=0.00001). These results provide support for the existence of a locus on the X chromosome that predisposes the FC to autism spectrum disorders.     

Analysis of chromosome 1 microsatellite markers and the FHM2-ATP1A2 gene mutations in migraine pedigrees

OBJECTIVES: The aims of the study were: (i) to extend our linkage analysis of chromosome 1q microsatellite markers in predominantly migraine with aura pedigrees and (ii) to test the novel FHM-2 ATP1A2 gene for involvement in these migraine affected pedigrees and a previous pedigree (MF14) showing evidence of linkage of markers to C1q31.METHODS: A chromosome 1 scan (31 markers) was performed in 21 multiplex pedigrees affected predominantly with migraine with aura (MA). The known FHM-2 ATP1A2 gene mutations were tested, by sequencing, for the involvement in MA and migraine without aura (MO) in these pedigrees. Sequencing was performed in the coding areas of the ATP1A2 gene through three MA individuals from MF14.RESULTS: Evidence for linkage was obtained at C1q23 to markers spanning the ATP1A2 gene. However, testing of the known ATP1A2 gene mutations (for FHM) in common migraine probands of pedigrees showing excess allele sharing was negative. Sequencing of the entire coding areas of the gene through all the three MA affected from MF14 was also negative for mutations.DISCUSSION: Microsatellite markers on chromosome 1q23 show evidence of excess allele sharing in MA and some MO pedigrees, suggesting linkage to the common forms of migraine and the presence of a susceptibility gene in this region. The FHM-2 (ATP1A2 gene) does not seem to be involved in the common types of migraine. Despite certain clinical characteristics, the genetic correlation between FHM and familial typical migraine remains unclear. Several candidate genes lie within the C1q23 and C1q31 cytogenetic regions; therefore, further studies are needed.     

Linkage analyses between dominant X-linked Charcot-Marie-Tooth disease, and 15 Xq11–Xq21 microsatellites in a new large family: Three new markers are closely linked to the gene

X-linked dominant inheritance was suspected in a large family with Charcot-Marie-Tooth disease since no male to male transmission was observed, and since the sensory and motor neuropathy was more severe in males than in females. To test linkage to the dominant X-linked Charcot-Marie-Tooth disease (DCMTX) locus in Xq13, genotypes of 19 affected and 19 unaffected individuals from this family were determined for 4 microsatellite markers. Close linkage to mfd66 (DXS453) was found by bipoint analysis (Zmax = 4.8 at θ = 0.00). Multipoint analysis mapped the gene between the androgen receptor and DXYS1. In addition, linkage analysis performed with 11 microsatellite markers, derived from a high density map spanning 16 cM on Xq11–Xq21 revealed 3 new tightly linked loci: afm287zgl (DXS1216), afm261zh5 and afm207zg5 (DXS995). Multipoint analysis localized the DCMTX gene to a 7.5 cM interval between afm123xd4 (DXS988) and afm116xg1 (DXS986). Combined analysis with these new microsatellites provides a powerful tool for carrier detection because of their high informativity and the small genetic distance (< 10 cM) between the markers flanking the gene.     

X-linked centronuclear myopathy: mapping the gene to Xq28.

The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness and primary asphyxia, has recently been mapped to Xq28. This report presents linkage analysis data of eight families with X-linked centronuclear myopathy. Four probes from the region Xq26-27 and five Xq28 probes were used to get more precise gene localization and marker order. St14 (DXS52), fully informative in all families, shows significant linkage to the CNM gene (z = 3.60; theta = 0.05), followed by DX13 (DXS15) (z = 2.03; theta = 0.06) and F8 (z = 1.86; theta = 0.00). Combination of the physical map derived by Kenwrick and Gitschier (1989) and our linkage data lead to the most probable order R/GCP-G6PD-(XLR-CNM-F8)-p767-St14-cpX67-++ +DX13 placing the CNM gene close to F8. The results of this study confirm strong linkage of the CNM gene to the region Xq28 and will permit carrier testing and prenatal diagnosis in CNM families. We conclude that the precise localization of this devastating disorder may be of great importance for genetic counselling in families at risk. The lack of information about gene frequency and mutation rate as well as the severity and burden of the disease point to the inevitable need for accurate clinical diagnosis.     

X-linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq

We examined a large family in which an X-linked recessive congenital ataxia manifested in 7 males from three generations. The affected boys first exhibited a marked delay of early developmental motor milestones. A neurological syndrome became evident by 5 to 7 years of age and included cerebellar ataxia, dysarthria, and external ophthalmoplegia; there were no symptoms of mental retardation, spastic paraparesis, or sensory loss. Neuroimaging studies revealed hypoplasia of cerebellar hemispheres and vermis. The disease showed no progression beyond early childhood. The unique heredity and clinical features clearly distinguish this new entity from a variety of previously described familial ataxias. Pairwise linkage analysis and haplotype reconstruction allowed us to map the gene responsible for this disorder to a 38-cM interval on chromosome Xp11.21-q24 flanked by the loci DXS991 and DXS1001. Upon multipoint linkage analysis, the disease gene was determined to be located most likely in the proximal part of chromosome Xq, with the maximal lod score of 4.66 at the locus DXS1059 (Xq23). This is the first example of the genetic mapping of a pure congenital cerebellar hypoplasia syndrome.     

HLA typing in the United Kingdom multiple sclerosis genome screen

The United Kingdom multiple sclerosis genome screen demonstrated a peak maximum lod score of 2.8 in the HLA region, together with statistically significant excess transmission of the 121-base pair (bp) allele of the tumour necrosis factor-a marker. In order to determine whether this association is independent of the established HLA association, or simply a consequence of the 121-bp allele being part of the same haplotype, we HLA-DR and -DQ typed the 227 sibling-pair families used in the original screen. The expected associations of multiple sclerosis with the DR15 (p=8.7E-18), DQ6 (p=2.0E-09) and DR51 (p=2.8E-16) phenotypes were confirmed, and excess transmission of the DRB1*1501 and DQB1*0602 alleles was demonstrated. Combining HLA typing with the original microsatellite data demonstrated extensive linkage disequilibrium between the 121-bp allele and the 1501-0602 haplotype. Outside this extended haplotype (121-1501-0602), none of the alleles demonstrated significant transmission distortion. Having established the importance of this extended haplotype, we reanalysed the entire genome screen data after excluding those sibling pairs sharing the extended haplotype (n=27). Conditioning the full genome screen data on the basis of identity by state sharing showed that some potential linkage regions identified in the original screen clustered in families, in which the extended haplotype was shared (1p, 2p and 17q), whereas others grouped with those in which it was not (5cen, 7p and Xq). This suggests complexity in the genetics of multiple sclerosis. Received: May 22, 1998 / Accepted: July 1, 1998 / Published online: December 9, 1998     

微卫星DNA DXS1113的多态性与心境障碍

目的 搜寻中国汉族人Ｘ染色体上的心境障碍（ＭＤ）易患性基因，探讨ＤＮＡＤＸＳ１１１３多态性与ＭＤ的关系及遗传学特征。方法 运用扩增片段长度多态性检测技术，分析８０例ＭＤ患者ＤＸＳ１１１３二核苷酸串联重复序的多态性分布，并以８０名正常人作为对照。结果 在对照组和ＭＤ组中检出１２种ＤＸＳ１１１３多态性片段，ＭＤ组与对照组之间有４种片段的差异有显著性。结论ＤＸＳ１１１３与ＭＤ关联，提示中国汉族人Ｘ染色体     

Evidence against close linkage of unipolar affective illness to human chromosome 11p markers HRAS1 and INS and chromosome Xq marker DXS52

The genetic basis of various subtypes of the affective disorders has been investigated by family, twin, and adoption studies, as well as by segregation and linkage analysis. Linkage analyses of bipolar disorder with the chromosome 11p15 DNA markers HRAS1 and INS, and the chromosome Xq28 markers for color blindness and G6PD have been reported. We have used restriction fragment length polymorphisms as markers to examine linkage in three extended families with unipolar affective illness, ascertained through probands with either recurrent unipolar or bipolar II illness. Using an inclusive definition of the affected phenotype, linkage could be excluded up to 28cM around the HRAS1-INS linkage group on chromosome 11p15, and up to 5 cM around the DNA marker DXS52 on Xq28. Negative linkage results were also obtained for two more restrictive definitions of affective illness. Thus, we find no evidence for the involvement of the chromosomal regions 11p15 and Xq28 with unipolar affective disorder in these three families.     

单纯型家族性发作性运动诱发性运动障碍二家系基因连锁分析

目的 对2个中国汉族单纯型发作性运动诱发性运动障碍(PKD)大家系进行排除定位,为PKD发病机制的探讨及疾病基因的克隆奠定基础.方法 抽取2个家系27名成员外周血,选取16号染色体上覆盖目前已知PKD位点的微卫星标记,进行参数及非参数连锁分析,并进行单体型分析.结果 通过对2个显性遗传的PKD大家系的参数及非参数连锁分析发现,家系A的最大LOD值以及NPL值均为负值,P＞0.05,排除与已知的PKD位点连锁;家系B的最大LOD值＜1,最大NPL值0.77,P＞0.05,不支持致病基因与已知PKD位点连锁.进一步对2个家系进行单体型分析,排除其致病基因位点与已知位点连锁,提示存在新的PKD疾病基因位点.结论 PKD具有遗传异质性,单纯型PKD家系存在新的疾病基因位点.     

Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family

We present a large kindred that contained patients with either adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN). The pedigree clearly supported the X-linked mode of inheritance of the nonneonatal form of ALD/AMN. Analysis with DNA markers at Xq28 suggested segregation of both ALD and AMN with an identical haplotype. This indicated that nonneonatal ALD and AMN are caused by a mutation in the same gene at Xq28. It showed, furthermore, that phenotypic differences between ALD and AMN are not necessarily the consequence of allelic heterogeneity due to different mutations within the same gene. The maximal lod score for linkage of the ALD/AMN gene and the multiallelic anonymous DNA marker at DXS52 was 3.0 at a recombination fraction of 0.00. This made a prenatal or presymptomatic diagnosis and heterozygote detection by DNA analysis with this marker reliable.     

Evidence of a founder haplotype refines the X-linked Charcot–Marie-Tooth (CMTX3) locus to a 2.5 Mb region

X-linked Charcot-Marie-Tooth (CMTX) disease is a common inherited degenerative disorder of the peripheral nerve. Previously, our laboratory identified a large New Zealand/United Kingdom (NZ/UK) family mapping to the CMTX3 locus (Xq26.3-27.1). We have now identified a second large, Australian X-linked CMT family that links to the CMTX3 locus. This new family has the same phenotype as our previously described CMTX3 family, with slightly milder disease in males than CMTX1 and asymptomatic carrier females. This study also includes the re-analysis of one of the original US pedigrees reporting the CMTX3 locus. The large Australian family shared the complete disease haplotype with our original NZ/UK family, while the American family shared only the distal portion of the disease haplotype. Comparison of the frequency of the CMTX3 haplotype to the normal population showed strong statistical evidence (p < 0.0001) indicating that the smaller shared haplotype is identical by descent. This suggests that the new CMTX3 family, our previously reported family, and the original American CMTX3 family have a common ancestor, and the disease in these families is caused by a founder mutation. The ancestral recombination observed in the American family refines the CMTX3 interval to a 2.5 Mb region between DXS984 and DXS8106. In this region, 11 out of the 15 annotated genes have been excluded for pathogenic mutations.     

Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

Schizophrenia is a highly heritable, severe psychiatric disorder affecting approximately 1% of the world population. A substantial portion of heritability is still unexplained and the pathophysiology of schizophrenia remains to be elucidated. To identify more schizophrenia susceptibility loci, we performed a genome-wide association study (GWAS) on 498 patients with schizophrenia and 2025 controls from the Han Chinese population, and a follow-up study on 1027 cases and 1005 controls. In the follow-up study, we included 384 single nucleotide polymorphisms (SNPs) which were selected from the top hits in our GWAS (130 SNPs) and from previously implicated loci for schizophrenia based on the SZGene database, NHGRI GWAS Catalog, copy number variation studies, GWAS meta-analysis results from the international Psychiatric Genomics Consortium (PGC) and candidate genes from plausible biological pathways (254 SNPs).Within the chromosomal region Xq28, SNP rs2269372 in RENBP achieved genome-wide significance with a combined P value of 3.98×10⁻⁸ (OR of allele A = 1.31). SNPs with suggestive P values were identified within 2 genes that have been previously implicated in schizophrenia, MECP2 (rs2734647, P _combined = 8.78×10⁻⁷, OR = 1.28; rs2239464, P _combined = 6.71×10⁻⁶, OR = 1.26) and ARHGAP4 (rs2269368, P _combined = 4.74×10⁻⁷, OR = 1.25). In addition, the patient sample in our follow-up study showed a significantly greater burden for pre-defined risk alleles based on the SNPs selected than the controls. This indicates the existence of schizophrenia susceptibility loci among the SNPs we selected. This also further supports multigenic inheritance in schizophrenia. Our findings identified a new schizophrenia susceptibility locus on Xq28, which harbor the genes RENBP, MECP2, and ARHGAP4.Key words: schizophrenia, genome-wide association study, Han Chinese, MECP2, ARHGAP4, RENBP     

Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean hispanics with familial Alzheimer disease

OBJECTIVES: To identify novel candidate regions for late-onset Alzheimer disease (LOAD) and to confirm linkage in previously identified chromosomal regions. DESIGN: Family-based linkage analysis. SETTING: Probands with familial LOAD identified in clinics in the Dominican Republic, Puerto Rico, and the United States. Patients We conducted a genome scan in 1161 members primarily clinically diagnosed as having LOAD; these members were from 209 families of Caribbean Hispanic ancestry. MAIN OUTCOME MEASURES: We analyzed 376 microsatellite markers with an average intermarker distance of 9.3 centimorgan. We conducted linkage analysis using possible and probable LOAD, and we performed affecteds-only 2-point linkage analyses assuming either an autosomal dominant or a recessive model. Subsequently, we conducted a multipoint affected sibling pair linkage analysis. RESULTS: Two-point parametric linkage analysis identified a locus at 3q28 with a genomewide empirical P value of .03 (logarithm of odds [LOD], 3.09) in a dominant model for probable and possible LOAD. Other regions suggestive of linkage included 2p25.3 (LOD, 1.77), 7p21.1 (LOD, 1.82), and 9q32 (LOD, 1.94). Under a recessive model, we also identified loci at 5p15.33 (LOD, 1.86), 12q24.21 (LOD, 2.43), 14q22.3 (LOD, 2.53), and 14q23.1 (LOD, 2.16) as suggestive for linkage. Restricted to probable LOAD, many of these loci continued to meet criteria suggestive for linkage, as did loci at 2p25.3 (LOD, 2.72), 3q28 (LOD, 2.28), 6p21.31 (LOD, 2.19), and 7p21.1 (LOD, 2.05). APOE conditional analysis indicated that the observed linkage at 3q28 was independent of the APOE epsilon4 allele. Multipoint nonparametric affected sibling pair linkage analysis provided confirmation of suggestive linkage for most, but not all, loci. CONCLUSIONS: Seven loci with LOD scores greater than 2.0 were identified among multiple affected Caribbean Hispanic families with LOAD. The highest LOD score was found at chromosome 3q28. At least 2 other independent studies have observed support for significant linkage at chromosome 3q28, highlighting this region as a locus for further genetic exploration.     

Analysis of HLA-DRB3 alleles and supertypical genotypes in the MHC Class II region in sporadic inclusion body myositis

We compared the carriage frequencies of HLA-DRB3 and its major alleles and of HLA-DRB4 and HLA-DRB5 in an Australian sIBM cohort and a population control group who had previously been genotyped for the HLA-DRB1*03:01 risk allele. There was a strong disease association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. The carriage of HLA-DRB4 was found to be strongly protective and abrogated the risk effect of HLA-DRB1*03:01. The findings indicate that haplotypic combinations of alleles at the HLA-DRB1 and secondary HLA-DRB loci have important risk modifying effects in sIBM.     

A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity

The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD_max score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ～20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ～28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society