Maximum LOD Score Research Articles

Re-assigning the DFNB33 locus to chromosome 10p11.23–q21.1

Homozygosity mapping is a powerful resource for mapping and identifying loci and genes responsible for autosomal recessive disorders. Nevertheless, it could result in the identification of several homozygous regions unrelated to the disease locus or non-informative regions. Previously, a genome-wide screen in a large consanguineous Jordanian family allowed us to assign the DFNB33 locus to chromosome 9q34.3. Sequencing of 23 candidate genes showed 11 SNPs in a heterozygous state in affected individuals. These results ruled out the candidate region on chromosome 9. Using additional markers, we were able to restrict the disease locus to an approximately 14 cM region at chromosome 10, located between markers D10S193 and D10S1784. A maximum LOD score of 3.99 was obtained with two markers, D10S199 and D10S220. The screening of two candidate genes, CX40.1 and FXYD4, failed to reveal any disease-causing mutations.

Mapping a New Familial Thyroid Epithelial Neoplasia Susceptibility Locus to Chromosome 8p23.1-p22 by High-Density Single-Nucleotide Polymorphism Genome-Wide Linkage Analysis

Familial nonmedullary thyroid carcinoma (FNMTC) accounts for approximately 5% of all thyroid tumors. Genetic mapping studies have identified four different chromosomal regions predisposing to FNMTC: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32), and TCO (19p13.2). Our objective was to map the gene predisposing to familial thyroid epithelial neoplasia in a large Portuguese family. The clinical screening of a Portuguese family identified 11 members affected with benign thyroid lesions and five affected with thyroid carcinomas. Linkage analysis excluded the involvement of the fPTC/PRN, NMTC1, MNG1, and TCO loci. To map the gene predisposing to thyroid epithelial neoplasia in this family, a genome-wide linkage analysis was conducted, using DNA samples from 17 family members and high-density single-nucleotide polymorphism arrays. A genome-wide significant evidence of linkage, to a single region on chromosome 8p23.1-p22 was obtained, with a maximum parametric haplotype-based LOD score of 4.41 (theta=0.00). Linkage analysis with microsatellite markers confirmed linkage to 8q23.1-p22, and recombination events delimited the minimal region to a 7.46-Mb span. Seventeen suggestive candidate genes located in the minimal region were excluded as susceptibility genes by mutational analysis. Allelic losses in the 8p23.1-p22 region were absent in seven thyroid tumors from family members, suggesting that the inactivation of a putative tumor suppressor gene may have occurred through other mechanisms. Our results present evidence for the existence of a novel familial thyroid epithelial neoplasia susceptibility locus on chromosome 8p23.1-p22, providing the basis for the identification of a gene for this disease.

Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9

BackgroundFrontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND.MethodsClinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing.ResultsNeuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree.ConclusionOur reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.

A linkage analysis of cigarette and alcohol consumption in an unselected Mexican American population

The use of alcohol and tobacco is highly prevalent. Studying the rate of consumption in a non-selected population could contribute to the elucidation of pathways involved in addiction or to the development of prevention programs. The San Antonio Family Heart Study has approximately 1,400 members with longitudinal data and did not select the proband with regard to exposure status. The goal of this study was to perform genome-wide linkage analysis of the rate of alcohol and cigarette consumption in a "normal" population. We used SOLAR to perform variance-components based analysis of the transformed maximal rate of consumption. Despite estimated heritabilities of 0.52 (P < 0.001) for cigarette and 0.39 (P < 0.001) for alcohol consumption, univariate linkage analyses produced only suggestive LOD scores, however the second suggestive linkage peak for the alcohol phenotype was present at 148 cM on chromosome 10, in the exact vicinity of the peak for the cigarette phenotype. In a bivariate analyses, the environmental correlation between alcohol and cigarette consumption was not significantly different from zero (rho(e) = -0.15, P = 0.18) and the overall genetic correlation was not different from zero (rho(g) = 0.16, P = 0.34). The results from the bivariate linkage analysis found a maximum LOD score of 3.82 (genome-wide P = 0.0054) at 151 cM on chromosome 10, at the location of the overlapping peaks from the univariate analyses.

High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density

A quantitative trait locus (QTL) for BMD maps to chromosome 1p36. We have analyzed a high density SNP panel from this region for linkage and association to BMD in 39 osteoporosis pedigrees. Our results support the presence of genes controlling BMD on 1p36 and indicate new candidates for further analyses. Low BMD is one of the major risk factors for osteoporosis. Following a genome scan in a sample of Caucasian families recruited through probands with low BMD, a region on 1p36 near marker D1S214 received support as a QTL for BMD from linkage (maximum lod-score = 2.87) and linkage disequilibrium (LD) analysis (p < 0.01). To better characterize the genetic risk factors for low BMD located in this genomic region, we have genotyped the same group of families for 1095 SNPs located across 11 Mb on 1p36. Linkage and LD analyses have been performed using the variance component approach. Multivariate linkage analysis indicated two QTLs for femoral neck BMD, lumbar spine BMD and trochanter BMD simultaneously on 1p36, with maximum lod-scores of 4.37 at 12 cM and 3.59 at 22 cM. LD analysis identified several SNPs potentially associated with BMD, including the RERE gene SNP rs11121179 (p = 0.000005 for lumbar spine BMD). Other candidate genes include G1P2, SSU72 and CCDC27 (each containing 1 SNP with p < 0.001 for at least one BMD trait). This study supports the presence in 1p36 of QTLs affecting BMD at multiple skeletal sites. Replication of our results in other independent cohorts is warranted.

Predicting the number and sizes of IBD regions among family members and evaluating the family size requirement for linkage studies

With genotyping of high-density single nucleotide polymorphisms (SNPs) replacing that of microsatellite markers in linkage studies, it becomes possible to accurately determine the genomic regions shared identity by descent (IBD) by family members. In addition to evaluating the likelihood of linkage for a region with the underlining disease (the LOD score approach), an appropriate question to ask is what would be the expected number and sizes of IBD regions among the affecteds, as there could be more than one region reaching the maximum achievable LOD score for a given family. Here, we introduce a computer program to allow the prediction of the total number of IBD regions among family members and their sizes. Reversely, it can be used to predict the portion of the genome that can be excluded from consideration according to the family size and user-defined inheritance mode and penetrance. Such information has implications on the feasibility of conducting linkage analysis on a given family of certain size and structure or on a few small families when interfamily homogeneity can be assumed. It can also help determine the most relevant members to be genotyped for such a study. Simulation results showed that the IBD regions containing true mutations are usually larger than regions IBD due to random chance. We have made use of this feature in our program to allow evaluation of the identified IBD regions based on Bayesian probability calculation and simulation results.

Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer

Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500-2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron-exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of alpha-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.

‘Linkage Analysis of Thyroid Antibody Production: Evidence for Shared Susceptibility to Clinical Autoimmune Thyroid Disease

Epidemiological data suggest a genetic susceptibility to thyroid antibody (TAb) production. The objective of the study was to identify genetic loci that are linked with TAb production. The design of the study was a whole genome linkage study in families with clustering of thyroid autoimmunity. The study took place at an academic medical center. Participants included 102 multigenerational families (540 individuals) multiplex for autoimmune thyroid disease (AITD) and TAb production. We computed two-point logarithm of odds (LOD) scores and multipoint heterogeneity LOD scores for 400 microsatellite markers spanning the entire human genome at an average distance of 10 cm (approximately 10 Mb). Three loci showed evidence for linkage with TAb production: 1) 2q locus, which gave a maximum multipoint heterogeneity LOD score (HLOD) of 2.8 and contained the CTLA-4 gene, previously reported to be linked and associated with clinical AITD; (2) 6p locus (HLOD 2.5), which was the same AITD-1 locus found to be linked with clinical AITD; and (3) 8q locus (HLOD 2.2), which contained the thyroglobulin gene, also previously reported to be linked and associated with AITD. All loci that were linked to TAb were also linked to AITD, suggesting that TAb and AITD share the same genetic predisposition. We conclude that: 1) some of the genes/loci predisposing to TAb and AITD are shared, whereas distinct genes/loci also exist; (2) the presence of TAb in relatives of AITD patients may be associated with increased risk for the development of clinical AITD; and (3) further studies are needed to determine the predictive value of TAb levels for the development of clinical AITD in relatives of patients with familial AITD.

High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach.

OBJECTIVE— Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes.RESEARCH DESIGN AND METHODS— To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis. In weighing the evidence for linkage, we considered maximum logarithm of odds score (maximum likelihood score [MLS]) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package SPLAT.RESULTS— Our primary finding for diabetic nephropathy, broadly defined, is on chromosome 19q (MLS = 3.1), and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of discordant sibpairs based on whether disease had progressed to ESRD suggested four tertiary peaks on chromosome 1q (ESRD only), chromosome 20p (proteinuria only), and chromosome 3q (two loci 58 cm apart, one for ESRD only and another for proteinuria only). Additionally, analysis of 130 ASPs for type 1 diabetes confirmed the linkage to the HLA region on chromosome 6p (MLS = 9.2) and IDDM15 on chromosome 6q (MLS = 3.1).CONCLUSIONS— This study identified several novel loci as candidates for diabetic nephropathy, none of which appear to be the sole genetic determinant of diabetic nephropathy in type 1 diabetes. In addition, this study confirms two previously reported type 1 diabetes loci.

Familial pure paroxysmal kinesigenic dyskinesia in Han population from the Chinese mainland: A new subtype?

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurologic inherited disease with heterogeneity. Autosomal dominant (AD) is the common inherited mode. There have been two loci mapped to 16 chromosome for PKD. However, no gene responsible for it has been identified so far. We collected 6 pedigrees from Chinese mainland. There were 122 members in all, including 26 affected. According to New diagnostic criteria of Bruno, they were diagnosed as pure PKD. From the clinic data, we found that the onset age was earlier and the severity was increasing in the subsequent generations in 4 pedigrees of them, which suggested genetic anticipation. Linkage analysis was applied in 2 of these pedigrees. The maximum LOD score and NPL score were negative. The followed haplotypes analysis excluded the PKD locus in both families from chromosome 16, providing evidence for a novel locus.

Identification of a Genetic Locus for Ichthyosis Vulgaris on Chromosome 10q22.3–q24.2

Ichthyosis vulgaris (IV) is one of the most commonly inherited disorders and has an estimated prevalence rate of 2.29% in China. To date, only one gene responsible for IV, the filaggrin gene (FLG), was identified, but genetic heterogeneity exists. In this study, two Chinese families with autosomal-dominant IV were genetically characterized. The FLG gene was first excluded as the disease-causing gene in the two families. The larger family was then characterized by genome-wide linkage analysis to identify a new genetic locus for IV. Significant linkage was identified with markers on chromosome 10q22.3-q24.2 with a maximum LOD score of 3.19. No other markers showed a LOD score of >1.5. Fine mapping defined the new genetic locus within a 20.7 cM region between markers D10S569 and D10S1709. The second family also showed positive linkage to the same 10q22.3-q24.2 region. The combined maximum LOD score in the two families was 3.95. Identification of linkage in two independent families provides strong genetic evidence that a previously unreported gene for IV is located on chromosome 10q22.3-q24.2. Future studies of the candidate genes at the 10q IV locus will identify a specific gene, which will provide insights into the pathogenesis of IV.

Gene mapping in a Chinese family with autosomal dominant centralpuiverulent cataract

Mapping the mutation gene for a Chinese family with autosomal dominant cataract. It was a retrospective study. Thirty-two individuals in this family, including fifteen patients, eight normal siblings and nine spouses, were investigated and 8 ml blood was collected from each member under informed consent. Genomic DNA of all 29 members was isolated by standard protocol. A genome wide scan was performed after PCR amplification for microsatellite makers on autosomal chromosomes. LOD score was calculated by Linkage 5. 1 and GeneHunter software. Positive Lod score were obtained in 10 microsatellite makers (D20S186, D20S163, D20S915, D20S152, D20S98, D20S904, D20S875, D20S112, D20S1140, D20S432) on chromosome 20q, and the maximum LOD score with D20S904 was 6.02. Haplotype construction and multipoint analysis mapped the mutation gene in this inherited cataract family to the chromosome 20p12. 1-20p11.23 region between D20S186 and D20S912, which is an approximately 5.47 centimorgan length. This is the second congenital cataract locus linked to chromosome 20q.

Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation

Split-Hand/Foot Malformation (SHFM) is a complex limb malformation affecting the central rays of the autopod. We studied a large consanguineous kindred afflicted with autosomal recessive SHFM. Twelve affected members had central feet reductions with or without hand involvement while the remaining one had the mildest phenotype and atypical SHFM. We identified by homozygosity mapping a novel SHFM locus at 12q13.11-q13 with a maximum multipoint lod score of 5.47 and by subsequent candidate gene approach a homozygous missense WNT10b mutation (p.R332W) in all affected individuals but the atypical case plus in an asymptomatic female. We propose that either a second locus contributes to the manifestation of SHFM phenotype or a suppressor locus prevented trait manifestation in the non-penetrant female. We also investigated linkage to the five known SHFM loci. Four of the loci were excluded, while in TP63 [tumor protein p63 (SHFM4)], the only known gene responsible for SHFM, we detected in most affected subjects a rare insertion variant (rs34201045) at the alternate promoter used for transcription of the N-terminal-truncated p63 isotype. This is the first reported WNT10b mutation on the pathogenesis of limb development and recessive mutation in SHFM.

Ordered subsets linkage analysis of antisocial behavior in substance use disorder among participants in the collaborative study on the genetics of alcoholism

Heterogeneity in complex diseases such as Substance Use Disorder (SUD) reduces the power to detect linkage and makes replication of findings in other populations unlikely. It is therefore critical to refine the phenotype and use methods that account for genetic heterogeneity between families. SUD was operationalized as diagnosis of abuse or dependence to alcohol and/or any one of five illicit substances. Whole-genome linkage analysis of 241 extended pedigree families from the Collaborative Study on the Genetics of Alcoholism was performed in Merlin using an affected sibship design. An Ordered Subsets Analysis (OSA) using FLOSS sought to increase the homogeneity of the sample by ranking families by their density of childhood and adult antisocial behaviors, producing new maximum Nonparametric Lod (NPL) scores on each chromosome for each subset of families. Prior to OSA, modest evidence for linkage was found on chromosomes 8 and 17. Although changes in NPL scores were not statistically significant, OSA revealed possible evidence of linkages on chromosome 7, near markers D7S1795 and D7S821. NPL scores >3.0 were also observed on chromosomes 2, 3, 5, 9, and 14. However, the number of families used in these latter subsets for linkage may be too small to be meaningful. Results provide some evidence for the ability of OSA to reduce genetic heterogeneity, and add further support to chromosome 7 as a possible location to search for genes related to various SUD related processes. Nonetheless, replication of these results in other samples is essential.

A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1–17p13.3

Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2-q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1-17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected.

Use of a genome-wide linkage screen to identify a hereditary neuroblastoma predisposition locus at chromosome 2p24–23

10010 Background: A subset of neuroblastomas show inheritance as an autosomal dominant trait with incomplete penetrance. Familial neuroblastoma is often lethal during childhood, resulting in very few pedigrees of sufficient size for linkage analysis. Low-resolution genetic approaches have not been successful in identifying a narrow genomic region consistent with linkage, a critical first step in identifying the causal gene. Methods: We performed a genome-wide scan for linkage in eighteen neuroblastoma pedigrees at ∼6000 single nucleotide polymorphisms. Parametric and non-parametric analyses were used to identify and refine candidate regions. Candidate genes were resequenced in a panel of 15 probands using Sanger-based or 454 technology. Results: We discovered a highly significant linkage signal covering a 34 Mb region on chromosome 2p with a maximum non-parametric LOD score of 4.23 (p=0.00001), and 13/18 families screened were consistent with linkage to this locus. No other genomic region was suggestive of linkage in these families, including previously identified 4p16 and 16p12–13 loci. To further refine the 2p region, we performed parametric analyses in which we varied gene frequency and penetrance assumptions across a broad range. All analyses supported the initial inference of linkage, with a maximized LOD score of 6.37 (p=0.0000019) at rs1344063. By mapping informative recombination events, we defined a 16 Mb putative predisposition locus at 2p24–23, a region that includes the MYCN oncogene. Resequencing of an 18 Kb region surrounding the MYCN gene in probands from each linked family showed no activating mutations or novel sequence variations. Resequencing of other neurodevelopmental regulatory genes including NAG, DDX1, GDF7, and OSR1 has excluded these as neuroblastoma predisposition genes. Results of ongoing resequencing of a prioritized list of positional candidates will be reported. Conclusions: A hereditary neuroblastoma predisposition gene is located within a 16 Mb region at 2p24–23. We speculate that inactivation of this gene may also influence the development of non-familial human neuroblastomas. No significant financial relationships to disclose.

A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans

Telomeres are repetitive sequences of variable length at the ends of chromosomes involved in maintaining their integrity. Telomere dysfunction is associated with increased risk of cancer and other age-related diseases. Telomere length is an important determinant of telomere function and has a strong genetic basis. We previously carried out a genome-wide linkage analysis of mean leukocyte telomere length, and identified a 12 cm quantitative-trait locus affecting telomere length on human chromosome 12. In the present study we confirmed linkage to this locus in an extended sample (380 families, 520 sib-pairs, maximum LOD score 4.3). Fine-mapping identified a 51 kb region of association within intron 1 of the Bicaudal-D homolog 1 (BICD1, MIM 602204) gene. The strongest association (P = 1.9 x 10(-5)) was with SNP rs2630578 where the minor allele C (frequency 0.21) was associated with telomeres that were shorter by 604 (+/-204) base pairs, equivalent to approximately 15-20 years of age-related attrition in telomere length. Subjects carrying the C allele for rs2630778 had 44% lower BICD1 mRNA levels in their leukocytes compared with GG homozygotes (P = 0.004). BICD1 is involved in Golgi-to-endoplasmic reticulum vacuolar transport. Previous studies have implicated vacuolar genes in telomere length homeostasis in yeast. Our study indicates that BICD1 plays a similar role in humans.

Genome‐wide scan in 124 Indonesian sib‐pair families with schizophrenia reveals genome‐wide significant linkage to a locus on chromosome 3p26‐21

Variation in incidence of schizophrenia between populations with different ethnical background may reflect population specific differences in nature and composition of genetic and environmental factors. In order to investigate whether there are population specific susceptibility genes for schizophrenia, we collected in Indonesia families with two or more affected siblings and, as far as available, parents and unaffected siblings, suitable for genetic linkage- and association studies. After checking extensively for incompatibilities with Mendelian inheritance as well as for errors in sampling, we used 124 families from the sample of 152 originally ascertained families for linkage analysis. Genotyping was performed at the NHLBI Mammalian Genotyping Service at Marshfield Research Organisation using the Screening Set 16, which comprises 402 Short Tandem Repeat Polymorphisms (STRPs). The genotypes of 540 individuals including 267 affected with schizophrenia were used for analysis. Multipoint sib-pair linkage analysis was carried out by estimation of--allele sharing derived--maximum likelihood LOD scores (MLS) in 154 sib-pair combinations. We obtained a genome-wide significant MLS of 3.76 on chromosome 3p26.2-25.3. Genome-wide significance was estimated by performing 10,000 simulated genomescans. Additional loci were detected on 1p12, which produced suggestive evidence for linkage (MLS = 2.35), as well as on 5q14.1 (MLS = 1.56), 5q33.3 (MLS = 1.11), and 10q (MLS = 1.17), where linkage had been reported previously. In conclusion, our study detected a region with genome-wide significant linkage, which will serve as starting point for identification of schizophrenia susceptibility genes in the Indonesian population.

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1

Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes (SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3-p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897 (theta = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP.

A Genome-wide Scan Maps a Novel High Myopia Locus to 5p15

This study was conducted to investigate the genetic component of three Chinese pedigrees originating from Hong Kong with autosomal dominant high myopia. A whole-genome scan was performed by using microsatellite markers spanning the whole genome with an average spacing of 10 cM. Regions containing markers that yielded LOD scores >1.0 were further analyzed by fine mapping with additional microsatellite markers. Fine-scale mapping of the linkage region was performed by genotyping a set of gene-based SNP markers on a cohort of 94 high myopia cases and 94 control subjects. Two-point LOD scores >1 were observed at markers D5S630, D5S416, D7S510, D11S908, and D17S944. Additional microsatellite markers flanking D5S630 revealed a maximum two-point LOD score of 4.81 at D5S2505 at theta = 0.00. Haplotype analysis narrowed the linkage region to 5p15.33-p15.2 with a 17.45-cM interval. The coding sequences of five genes located within this region, IRX2, IRX1, POLS, CCT5, and CTNND2, were screened. No segregation of polymorphism with high myopia was found. Genotyping of 41 SNPs within this region in a Chinese cohort of 94 high myopia cases and 94 control subjects showed that the allele and genotype distributions of one SNP, rs370010, was different between cases and controls (genotype P = 0.01176, allele P = 0.00271 and trend P = 0.00375), but such association did not remain significant after false discovery rate (FDR) correction. This SNP is located within a hypothetical gene LOC442129. A novel autosomal dominant high myopia locus was mapped on chromosome 5p15.33-p15.2 with an interval of 17.45 cM.