偏执型与未分化型精神分裂症家系两个靶染色体易感位点的连锁分析

目的 探讨中国人群中精神分裂症亚型与1号染色体长臂1q21-25和6号染色体短臂6p21-25易感基因位点的相关性.方法 在染色体1q21-25区域中选择5个微卫星标记和6p21-25区域中选择8个微卫星标记对36个来自中国河南省的精神分裂症家系(19个偏执型和17个未分化型)中的242个个体进行基因分型及参数和非参数连锁分析.结果 36个精神分裂症家系的1号染色体参数分析时,在显性遗传模式下,D1S484得到多点异质性对数优势记分法(heterogeneity Log of odds score method,HLOD)值为1.33 (α=0.38).非参数分析时,在D1S484得到多点非参数连锁(nonparametric linkage,NPL)值为1.89(P=0.0188);D1S2878单点NPL值为2.11(P=0.0111),多点NPL值为2.41(P=0.0053);D1S196多点NPL值为1.59(P=0.0383).提示以上3个位点存在连锁.在17个未分化型家系中,D1S484多点NPL值为1.60(P=0.0367);D1S2878单点 NPL值为1.95(P=0.0145),多点NPL值为2.39(P=0.0041); D1S196多点NPL值为 1.74(P=0.0255).这与以上36个家系提示连锁的位点相同.在19个偏执型家系中,5个微卫星标记位点均未提示连锁.36个精神分裂症家系的6号染色体分析发现,除19个偏执型精神分裂症家系参数连锁分析在隐性模式下D6S289位点单点HLOD值为1.26(α=0.40),多点HLOD值为1.12(α=0.38)和非参数连锁分析在D6S289位点单点NPL值为1.52(P=0.0402),多点NPL值为1.92(P=0.0206)之外,36个精神分裂症家系总体分析和其中17个未分化型家系分型分析的结果显示8个微卫星标记位点均未提示有连锁.结论 在染色体1q23.3 和1q24.2区域可能存在与中国河南省未分化型精神分裂症相关的易感基因;在6p23区域可能存在与偏执型精神分裂症相关的易感基因.

Abstract：

Objective To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. Methods A genomic scan and parametric and non-parametric analyses were performed on 242 individuals from 36 schizophrenia pedigrees, including 19 paranoid schizophrenia and 17 undifferentiated schizophrenia pedigrees, from Henan province of China using 5 microsatellite markers in the chromosome region 1q21-25 and 8 microsatellite markers in the chromosome region 6p21-25, which were the candidates of previous studies. All affected subjects were diagnosed and typed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-Ⅳ-TR; American Psychiatric Association, 2000). All subjects signed informed consent. Results In chromosome 1, parametric analysis under the dominant inheritance mode of all 36 pedigrees showed that the maximum multi-point heterogeneity Log of odds score method (HLOD) score was 1.33 (α=0.38). The non-parametric analysis and the single point and multi-point nonparametric linkage (NPL) scores suggested linkage at D1S484, D1S2878, and D1S196. In the 19 paranoid schizophrenias pedigrees, linkage was not observed for any of the 5 markers. In the 17 undifferentiated schizophrenia pedigrees, the multi-point NPL score was 1.60 (P=0.0367) at D1S484. The single point NPL score was 1.95 (P=0.0145) and the multi-point NPL score was 2.39 (P=0.0041) at D1S2878. Additionally, the multi-point NPL score was 1.74 (P=0.0255) at D1S196. These same three loci showed suggestive linkage during the integrative analysis of all 36 pedigrees. In chromosome 6, parametric linkage analysis under the dominant and recessive inheritance and the non-parametric linkage analysis of all 36 pedigrees and the 17 undifferentiated schizophrenia pedigrees, linkage was not observed for any of the 8 markers. In the 19 paranoid schizophrenias pedigrees, parametric analysis showed that under recessive inheritance mode the maximum single-point HLOD score was 1.26 (α=0.40) and the multi-point HLOD was 1.12 (α=0.38) at D6S289 in the chromosome 6p23. In nonparametric analysis, the single-point NPL score was 1.52 (P=0.0402) and the multi-point NPL score was 1.92 (P=0.0206) at D6S289. Conclusion Susceptibility genes correlated with undifferentiated schizophrenia pedigrees from D1S484, D1S2878, D1S196 loci, and those correlated with paranoid schizophrenia pedigrees from D6S289 locus are likely present in chromosome regions 1q23.3 and 1q24.2, and chromosome region 6p23, respectively.     

Linkage of schizophrenia with chromosome 1q32 in Korean multiplex families.

Chromosome 1q contains a few loci for which modest evidence of linkage with schizophrenia has been reported in several independent studies. However, markers showing the peak linkage signal are dispersed over a large chromosomal region. In addition, inconsistent findings have been generated from different populations or different subgroups of the same populations. The purpose of the current study is to determine whether those loci are linked to schizophrenia in the Korean population. We investigated 46 Korean multiplex schizophrenia families, initially using 11 microsatellite markers spanning around 91 cM region of 1p22 approximately 42. In a non-parametric linkage analysis, D1S249 located on 1q32.1 showed statistical evidence suggestive of linkage. At the second stage analysis for narrowing down the region, four additional nearby markers were genotyped. In the single point analysis, we found another suggestive linkage signal at D1S2891. The highest NPL score of 2.67 (P = 0.0039) was obtained in the multi-point analysis. This study provides supportive evidence for linkage of chromosome 1q32 with schizophrenia.     

Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families.

Positive linkage of schizophrenia to chromosome 8p22-21 loci had been reported in the Caucasian samples. This study was designed to replicate this finding by using eleven microsatellite markers on chromosome 8p22-21 in 52 Taiwanese schizophrenic families with at least two affected siblings. Two phenotype models (narrow: DSM-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other non-affective psychotic disorders) were used to define the disease phenotype. Maximum non-parametric linkage scores (NPL score) of 2.45 (P = 0.008) and 1.89 (P = 0.02) were obtained for the marker D8S1222 under the broad and narrow models, respectively. Positive linkage was found across about a 4-cM region. The marker D8S1222 was about 400 kbp distal to the exon 1 of glial growth factor 2 (GGF2), an isoform of Neuregulin 1 gene (NRG1), which has been highly suggested to be a candidate gene for schizophrenia. The results provide suggestive linkage evidence of schizophrenia to loci near NRG1 on chromosome 8p21 in an ethnically distinct Taiwanese sample. Further exploration of the candidate gene and nearby chromosome regions is warranted.     

A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.     

Genome-wide linkage analysis of allergic rhinoconjunctivitis in a Swedish population

BACKGROUND: Allergic rhinoconjunctivitis is a common complex disorder characterized by itching and irritation in the nose, bouts of sneezing, watery rhinorrhoea, nasal congestion and itchy eyes with tears and swelling. Like other atopic disorders such as allergic asthma and atopic dermatitis, the development involves complex interactions of genes and environmental factors. OBJECTIVE: The purpose of this study was to identify susceptibility loci for allergic rhinoconjunctivitis. METHODS: We conducted a genome-wide linkage analysis using a non-parametric, affected-relative-pair method. The 250 families used were collected originally for an atopic dermatitis linkage study. RESULTS: Three regions showed favour in evidence of linkage to allergic rhinoconjunctivitis: 3q13 (D3S1278: logarithm of odds ratio (LOD)=1.64, P<0.003), 4q34-35 (D4S1652: LOD=1.49, P<0.005) and 18q12 (D18S535: LOD=1.94, P<0.002). In addition, four regions showed weaker evidence in favour of linkage: 6p22-24 (D6S1959: LOD=1.39, P<0.006), 9p11-q12 (D9S1118: LOD=1.15, P<0.02), 9q33.2-34.3 (D9S915: LOD=1.29, P<0.01) and 17q11.2 (D17S1294: LOD=1.13, P<0.02). In single-point analysis, one locus on chromosome 3 close to marker D3S1278 reaches the suggestive level (LOD=2.28, P<6 x 10(-4)) while one on chromosome 17 close to marker D17S921 almost reaches this level (LOD=2.17, P<8 x 10(-4), Table 3). CONCLUSION: Our results support the linkage to allergic rhinoconjunctivitis on 3q13, 6p23-p24 and 9q34.3 shown in previous investigations.     

A follow-up linkage study of Finnish pre-eclampsia families identifies a new fetal susceptibility locus on chromosome 18

Pre-eclampsia is a common vascular disorder of pregnancy. It originates in the placenta and targets the maternal endothelium. According to epidemiological research, >50% of the liability to this disorder can be accounted for by genetic factors. Both maternal and fetal genes contribute to the risk, but especially the fetal genetic risk profile is still poorly understood. We have previously detected linkage signals in multiplex Finnish families on chromosomes 2p25, 4q32, and 9p13 using maternal phenotypes. We performed a linkage analysis using updated maternal phenotypes and an unprecedented linkage analysis using fetal phenotypes. Markers genotyped were available from 237 individuals in 15 Finnish families, including 72 affected mothers and 49 affected fetuses. The MERLIN software was used for sample and marker quality control and linkage analysis. The results were compared against the original ones obtained by using the GENEHUNTER 2.1 software. The previous identification of the maternal susceptibility locus to a genetic location at 21.70 cM near marker D2S168 on chromosome 2 was confirmed by using both maternal and fetal phenotypes (maternal non-parametric linkage (NPL) score 3.79, P=0.00008, LOD (logarithm (base 10) of odds)=2.20 and fetal NPL score 2.95, P=0.002, LOD=1.71). As a novel finding, we present a suggestive linkage to chromosome 18 at 86.80 cM near marker D18S64 (NPL score 2.51, P=0.006, LOD=1.20) using the fetal phenotype. We propose that chromosome 18 may harbor a new fetal susceptibility locus for pre-eclampsia.     

Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval

We previously reported an autosomal scan for schizophrenia susceptibility loci in a systematically recruited sample of Arab Israeli families. The scan detected significant evidence for linkage at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) and a multipoint parametric LOD score of 4.16. In order to refine this finding we typed 42 additional microsatellite markers on chromosome 6q between D6S1570 (99.01 cM from the pter) and D6S281 (190.14 from the pter) in the same sample (average intermarker distance approximately 1.7 cM). In the 23 cM region between D6S1715 and D6S311, markers were more closely spaced ( approximately 1.1 cM). Multipoint nonparametric and parametric and single point linkage analyses were performed. The peak NPL rose to 4.98 (P=0.00000058) at D6S1626 (136.97 cM), immediately adjacent to D6S292 (NPL 4.98, P=0.00000068), the marker that gave the highest NPL in the original genome scan, under the broad diagnostic category. The putative susceptibility region (NPL-1) was reduced from 12.0 to 4.96 cM. The peak multipoint parametric LOD score was 4.63 at D6S1626 under a dominant genetic model, core diagnostic category and the LOD-1 interval was 2.10 cM. The maximum single point LOD score (3.55, theta=0.01) was also at D6S1626 (dominant model, core diagnostic category). Increased evidence for linkage in the same sample as in the original genome scan and consistent localization of the linkage peak add further support for the presence of a schizophrenia susceptibility locus at chromosome 6q23. Moreover, the markedly reduced linkage interval greatly improves prospects for identifying a schizophrenia susceptibility gene within the implicated region.     

Linkage analysis in bipolar pedigrees adds support for a susceptibility locus on 21q22

Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.     

A novel locus for autosomal dominant hereditary gingival fibromatosis, GINGF3, maps to chromosome 2p22.3-p23.3

Hereditary gingival fibromatosis (HGF) is a rare, benign disorder characterized by slowly progressive fibrous overgrowth of the gingiva. To date, two loci have been mapped in familial cases with autosomal dominant non-syndromic HGF: GINGF (MIM 135300) on chromosome 2p21-p22 and GINGF2 (MIM 605544) on chromosome 5q13-q22. Of the two loci, only SOS1 (son of sevenless one, MIM 182530) gene underlying GINGF locus has been identified. Ascertainment of a large Chinese family has allowed the mapping of a novel locus to 2p22.3-p23.3, GINGF3. Haplotype construction and analysis localized the new locus to an 11.4-cM interval between markers D2S2221 (telomeric) and D2S1788 (centromeric). The maximum two-point limit of detection (LOD) score of 3.45 (theta=0) and multipoint LOD score of 5.00 for marker D2S390 strongly supported linkage to this region. Thus, this genetic interval is distal to and does not overlap with the previously described locus, GINGF, on 2p21-p22.     

Genome scan for loci involved in nonsyndromic cleft lip with or without cleft palate in families from West Bengal, India

In order to identify genes or regions involved in nonsyndromic cleft lip with or without cleft palate (CL/P) in families from India, we analyzed 38 multiplex families (DNA from 272 individuals, 82 affected with CL/P, 190 unaffected) for 285 genome-wide markers (average spacing 12.6 cM), including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 that have been implicated in other studies of CL/P. LOD scores (two-point and multipoint), and model-free association (TDT) and linkage (NPL) statistics, were calculated between each of the markers and a hypothetical CL/P susceptibility locus. The most statistically significant two-point linkage results were with markers on chromosome 7 (LOD = 1.89 with D7S435, 7p15, 47 cM), chromosome 5 (LOD = 1.76 with D5S407, 5q11, 65 cM), chromosome 15 (LOD = 1.55 with D15S652, 15q26, 90 cM), and chromosome 20 (LOD = 1.46 with STS155130, 20q13, 54 cM). The most significant multipoint linkage result was on chromosome 5q, again near D5S407 (HLOD = 1.40). Regions on chromosomes 1p, 1q, 7q, 12q, 16q, 18q, and Xp also had a LOD or HLOD > or = 1.0. Of seven candidate markers and regions with previous positive reports in the literature (TGFA, MSX1, D4S175, F13A1, TGFB3, D17S250, and APOC2), none had a significant linkage result, but one (the APOC2 region) had a significant association result and three others (TGFA, MSX1, F13A1) had suggestive results. The results are consistent with the involvement of multiple loci in CL/P expression in this West Bengal population, which concurs with results found in other CL/P study populations.     

A novel susceptibility locus for Hirschsprung's disease maps to 4q31.3-q32.3

We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.     

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.     

Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe alpha1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV(1)) < 60% predicted, FEV(1)/FVC < 90% predicted], mild airflow obstruction (FEV(1) < 80% predicted, FEV(1)/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD.     

The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus.

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.     

Suggestive linkage of chromosome 10p to schizophrenia is not due to transmission ratio distortion

The genome scan of the European-American schizophrenia families from the Human Genetics Initiative of the National Institute of Mental Health (NIMH) reported a suggestive linkage to chromosome 10p. Subsequently, Paterson and Petronis [1999] reported evidence for transmission ratio distortion on 10p to females. They suggested that transmission ratio distortion to females might have created spurious evidence for linkage to 10p. To address this issue, we reanalyzed our 10p data using only male-male affected sibling pairs. The two chromosome 10p markers that gave the most evidence for linkage in our prior report continued to show evidence for linkage: D10S1423 (NPL Z = 3.0, P = 0.001) and its neighbor D10S582 (NPL Z = 2.9, P = 0.002). These data suggest that our prior report of suggestive linkage of schizophrenia to markers on 10p cannot be attributed to the transmission ratio distortion to females reported by Paterson and Petronis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:607-608, 1999.     

Linkage analyses of schizophrenia to chromosome 6p24-p22: An attempt to replicate

The present study evaluates evidence for linkage of schizophrenia to chromosome 6p24-p22. An independent sample of 211 families ascertained on the basis of having an affected sib-pair diagnosed with schizophrenia or schizoaffective disorder was assessed with seventeen polymorphic markers spanning a 37cM region. Linkage analysis was performed with parametric and non-parametric methods to test for cosegregation using 4 models of inheritance. Neither two-point nor multipoint non-parametric analyses reached significance at a level less than 0.01 for any markers examined in the region and lod score analyses were not suggestive of linkage. Based on initial findings in the present data set and recently published linkage results, two specific areas were densely covered with markers and tested for linkage disequilibrium. After correcting for multiple comparisons within each locus, no significant deviation from expected allele transmission ratios was observed. The present findings together with the published literature fail to find consistent evidence of a linkage for schizophrenia to a single locus on chromosome 6.     

Colobomatous macrophthalmia with microcornea syndrome maps to the 2p23-p16 region

Colobomatous macrophthalmia with microcornea syndrome (OMIM 602499) is a rare, autosomal dominant malformation characterized by microcornea, uveal coloboma, axial enlargement of the globe, and myopia. Using what is currently the largest described pedigree and candidate localization approach, we first excluded the candidate genes PAX2, PAX3, PAX6, and PAX9. Subsequently, the chromosome 14q24 region containing the CHX10, SIX1, and SIX4 genes were also excluded. Positive LOD scores were obtained with the DNA markers selected from the 2p23-p16 region. A maximum pairwise LOD score of 3.61 (Theta = 0) was noted with the DNA marker D2S1788. Haplotype analysis positioned the locus between DNA markers D2S2263 and D2S1352 within a 22 Mb physical interval. This region contains major candidate genes, such as SIX2, SIX3, and CYP1B1; however, mutation analysis did not identify a causative mutation in these genes. Macrophthalmia, colobomatous, with microcornea (MACOM) is proposed as the gene symbol for this malformation linked to 2p23-p16.     

Linkage genome scan for loci predisposing to panic disorder or agoraphobia

We conducted a 10 cM linkage genome scan in a set of 20 American pedigrees (153 subjects), ascertained through probands with panic disorder (PD). Several anxiety disorders segregate in these families; they were diagnosed on the basis of Schedule for Affective Disorders and Schizophrenia interview. In this article, we describe results for panic disorder and agoraphobia, which are closely related, common, heritable anxiety disorders. This is the first complete linkage genome scan for agoraphobia and the third for PD. A total of 407 markers (389 autosomal, 18 X chromosome) were genotyped. Multipoint LOD score and NPL analysis were completed using GENEHUNTER2. For PD, two genomic regions meet criteria for suggestive linkage. One of these regions is on chromosome 1 (LOD score = 2.04). This region coincides with a region that generated a LOD score of 1.1 in a previous genome scan by Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. The other (LOD score = 2.01) is located on chromosome 11p and occurs at marker CCKBR, one of eight candidate genes examined. For agoraphobia, the most promising potential linkage was on chromosome 3 (NPL score = 2.75; P = 0.005). This was accounted for primarily by a single family that by itself generated an NPL score of 10.01 (P = 0.0039) and a LOD score of 2.10. These results provide initial evidence for a genetic locus on chromosome 3 that contributes to risk for agoraphobia. They also support suggestive linkage to two risk loci for panic disorder. Additional potential loci were identified with lesser statistical support; several of these were consistent with previously reported panic disorder linkage results. Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci. Published 2001 Wiley-Liss, Inc.     

头颈部鳞癌的微卫星不稳定性和杂合性丢失的初步研究

目的:探讨头颈部鳞癌的微卫星不稳定性(MSI)及杂合性丢失(LOH)。方法:选择来自3、5、6、8、9、13、17和18号染色体的15个微卫星标志对36例头颈部鳞癌标本和相应的外周血进行微卫星分析。结果:36例头颈部鳞癌中,27.8%(10/36)分别有1-8个位点存在MSI,MSI发生率较高的位点为:D17S520(22.9%)、D6S105(16.7%)和D8S264(13.9%)。在9p21-p22和3p14等处存在一定的LOH。微卫星异常的检出率与肿瘤分期、分级无相关性。结论:提示MSI是头颈部鳞癌中较为常见的遗传学变化,染色体9p21-p22和3p14区域可能存在与头颈部鳞癌有关的抑癌基因。     

Genome search for susceptibility loci of common idiopathic generalised epilepsies

Genetic factors play a major role in the aetiology of idiopathic generalised epilepsies (IGEs). The present genome scan was designed to identify susceptibility loci that predispose to a spectrum of common IGE syndromes. Our collaborative study included 130 IGE-multiplex families ascertained through a proband with either an idiopathic absence epilepsy or juvenile myoclonic epilepsy, and one or more siblings affected by an IGE trait. In total, 413 microsatellite polymorphisms were genotyped in 617 family members. Non-parametric multipoint linkage analysis, using the GeneHunter program, provided significant evidence for a novel IGE susceptibility locus on chromosome 3q26 (Z(NPL) = 4.19 at D3S3725; P = 0.000017) and suggestive evidence for two IGE loci on chromosome 14q23 (Z(NPL) = 3.28 at D14S63; P = 0.000566), and chromosome 2q36 (Z(NPL) = 2.98 at D2S1371; P = 0.000535). The present linkage findings provide suggestive evidence that at least three genetic factors confer susceptibility to generalised seizures in a broad spectrum of IGE syndromes. The chromosomal segments identified harbour several genes involved in the regulation of neuronal ion influx which are plausible candidates for mutation screening.