Multipoint LOD Score Research Articles

Familial mesial temporal lobe epilepsy maps to chromosome 4q13.2-q21.3

To report results of linkage analysis in a large family with autosomal dominant (AD) familial mesial temporal lobe epilepsy (FMTLE). Although FMTLE is a heterogeneous syndrome, one important subgroup is characterized by a relatively benign course, absence of antecedent febrile seizures, and absence of hippocampal sclerosis. These patients have predominantly simple partial seizures (SPS) and infrequent complex partial seizures (CPS), and intense and frequent déjà vu phenomenon may be the only manifestation of this epilepsy syndrome. No linkage has been described in this form of FMTLE. We identified a four-generation kindred with several affected members meeting criteria for FMTLE and enrolled 21 individuals who gave informed consent. Every individual was personally interviewed and examined; EEG and MRI studies were performed on three affected subjects. DNA was extracted from every enrolled individual. We performed a genome-wide search using an 8 cM panel and fine mapping was performed in the regions with a multipoint lod score >1. We sequenced the highest priority candidate genes. Inheritance was consistent with AD mode with reduced penetrance. Eleven individuals were classified as affected with FMTLE and we also identified two living asymptomatic individuals who had affected offspring. Seizure semiologies included predominantly SPS with déjà vu feeling, infrequent CPS, and rare secondarily generalized tonic-clonic seizures. No structural abnormalities, including hippocampal sclerosis, were detected on MRI performed on three individuals. Genetic analysis detected a group of markers with lod score >3 on chromosome 4q13.2-q21.3 spanning a 7 cM region. No ion channel genes are predicted to be localized within this locus. We sequenced all coding exons of sodium bicarbonate cotransporter (SLC4A) gene, which plays an important role in tissue excitability, and cyclin I (CCNI), because of its role in the cell migration and possibility of subtle cortical abnormalities. No disease-causing mutations were identified in these genes. We report identification of a genetic locus for familial mesial temporal lobe epilepsy. The identification of a disease-causing gene will contribute to our understanding of the pathogenesis of temporal lobe epilepsies.

BRIEF NOTES: Elimination of neutrophil elastase and adaptor protein complex 3 subunit genes as the cause of trapped neutrophil syndrome in Border collies

Table S1 Microsatellite loci used to genotype 72 Border collies for autozygosity mapping and linkage analysis in the TNS pedigree. Table S2 Alleles for 12 microsatellite loci from five candidate regions in eight TNS affected dogs (537, 541, 577, 576, 621, 893, 1137 and 1151) with multipoint LOD scores for linkage of each of the microsatellites to TNS. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans

Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and systolic dysfunction. So far sixteen genes have been shown to cause autosomal dominant familial dilated cardiomyopathy (FDC). We identified a large Korean family from the Jeju island showing a clear Mendelian inheritance of FDC. A genomewide linkage scan at 9 cM marker density identified a peak multipoint LOD score of 2.82 at D1S195. Haplotyping of the region with 15 additional markers defined a candidate interval that included a known candidate gene encoding the lamin A/C (LMNA). Sequencing of the LMNA exons revealed one missense mutation at C568T (Arg190Trp) in the alpha-helical rod domain of the LMNA gene co-segregating with FDC with conduction-system disease. The same mutation was found in patients of another Korean family with FDC without conduction-system disease. Upon screening 14 sporadic DCM cases, we found three LMNA mutations including a case having a previously described (Glu161Lys) mutation and two having novel mutations (Glu53Val and Glu186Lys). Our results suggest that variable genotypes of laminopathy are implicated in not only familial but also considerable proportion of sporadic DCM.

Genomewide Scan for Linkage Reveals Evidence of Several Susceptibility Loci for Alopecia Areata

Alopecia areata (AA) is a genetically determined, immune-mediated disorder of the hair follicle that affects 1%-2% of the U.S. population. It is defined by a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body. In an effort to define the genetic basis of AA, we performed a genomewide search for linkage in 20 families with AA consisting of 102 affected and 118 unaffected individuals from the United States and Israel. Our analysis revealed evidence of at least four susceptibility loci on chromosomes 6, 10, 16 and 18, by use of several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint LOD score of 3.93 on chromosome 18, a two-point affected sib pair (ASP) LOD score of 3.11 on chromosome 16, several ASP LOD scores >2.00 on chromosome 6q, and a haplotype-based relative risk LOD of 2.00 on chromosome 6p (in the major histocompatibility complex locus). Our findings confirm previous studies of association of the human leukocyte antigen locus with human AA, as well as the C3H-HeJ mouse model for AA. Interestingly, the major loci on chromosomes 16 and 18 coincide with loci for psoriasis reported elsewhere. These results suggest that these regions may harbor gene(s) involved in a number of different skin and hair disorders.

A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13–16.1

Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3-0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published. In this study, a genome-wide linkage study was performed in a large Greek pedigree segregating autosomal dominant otosclerosis. A seventh locus, OTSC7, was localized on chromosome 6q13-16.1 with a multipoint LOD score of 7.5 in the 13.47 cM region defined by markers D6S1036 (centromeric) and D6S300 (telomeric). Linkage analysis of this new locus in 13 smaller Belgian and Dutch families has identified one family from The Netherlands in which allele segregation suggests linkage to this region. The overlap between the critical regions of these two families is a 1.06 Mb interval between the genetic markers D6S1036 (centromeric) and D6S406 (telomeric) on chromosome 6q13.

Genomewide Linkage Scan for Split–Hand/Foot Malformation with Long-Bone Deficiency in a Large Arab Family Identifies Two Novel Susceptibility Loci on Chromosomes 1q42.2-q43 and 6q14.1

Split-hand/foot malformation with long-bone deficiency (SHFLD) is a rare, severe limb deformity characterized by tibia aplasia with or without split-hand/split-foot deformity. Identification of genetic susceptibility loci for SHFLD has been unsuccessful because of its rare incidence, variable phenotypic expression and associated anomalies, and uncertain inheritance pattern. SHFLD is usually inherited as an autosomal dominant trait with reduced penetrance, although recessive inheritance has also been postulated. We conducted a genomewide linkage analysis, using a 10K SNP array in a large consanguineous family (UR078) from the United Arab Emirates (UAE) who had disease transmission consistent with an autosomal dominant inheritance pattern. The study identified two novel SHFLD susceptibility loci at 1q42.2-q43 (nonparametric linkage [NPL] 9.8, P=.000065) and 6q14.1 (NPL 7.12, P=.000897). These results were also supported by multipoint parametric linkage analysis. Maximum multipoint LOD scores of 3.20 and 3.78 were detected for genomic locations 1q42.2-43 and 6q14.1, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of the SHFLD loci to a region of approximately 18.38 cM (8.4 Mb) between single-nucleotide polymorphisms rs1124110 and rs535043 on 1q42.2-q43 and to a region of approximately 1.96 cM (4.1 Mb) between rs623155 and rs1547251 on 6q14.1. The study identified two novel loci for the SHFLD phenotype in this UAE family.

Autosomal Dominant Cornea Plana is not Associated with Pathogenic Mutations in DCN, DSPG3, FOXC1, KERA, LUM, or PITX2

Purpose: To determine the genetic basis of autosomal dominant cornea plana (CNA1) through the performance of a genome-wide linkage analysis and screening of the decorin (DCN), dermatan sulfate proteoglycan 3 (DSPG3), forkhead box C1 (FOXC1), keratocan (KERA), lumican (LUM,) and paired-like homeodomain transcription factor 2 (PITX2) genes in members of an affected multigenerational family. Methods: Cycloplegic refraction, slit lamp biomicroscopy, corneal pachymetry, and corneal topography were performed to determine each patient's affected status. DNA was obtained from affected and unaffected subjects for the performance of a genome-wide linkage analysis as well as PCR amplification and sequencing of DCN, DSPG3, FOXC1, KERA, LUM, and PITX2. Results: Five affected and three unaffected individuals were examined and provided a peripheral blood sample for DNA isolation. All affected individuals demonstrated an average corneal dioptric power less than 39 D, as well as one or more of the following anomalies: high hyperopia, strabismus, microcornea, posterior embryotoxon, iridocorneal adhesions, iris atrophy, and pupillary irregularities. A genome-wide linkage analysis did not indicate or exclude linkage to the region on chromosome 12 to which CNA1 has been previously mapped, and did not provide a single or multipoint LOD score greater than 2.0 for any of the 400 microsatellite markers. Screening of DCN, DSPG3, FOXC1, KERA, LUM, and PITX2 revealed 12 previously described single nucleotide polymorphisms, 2 previously described duplications, and 1 previously described insertion. None of the mutations previously associated with autosomal recessive cornea plana (CNA2) were identified. Seven novel sequence variants were described, including 5 single nucleotide substitutions, 1 insertion and 1 deletion. None of the identified sequence variants demonstrated complete segregation with the affected phenotype in the pedigree. Conclusion: Although missense and nonsense mutations in KERA are associated with CNA2, we did not identify any of the previously described mutations or novel mutations that segregated with the disease phenotype in a family with CNA1. In addition, no pathogenic sequence variations were found in DCN, DSPG3, LUM, PITX2 and FOXC1, which have also been implicated in corneal and anterior segment dysgenesis.

Phenotypic definition of Chiari type I malformation coupled with high‐density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15

Chiari type I malformation (CMI; OMIM 118420) is narrowly defined when the tonsils of the cerebellum extend below the foramen magnum, leading to a variety of neurological symptoms. It is widely thought that a small posterior fossa (PF) volume, relative to the total cranial volume leads to a cramped cerebellum and herniation of the tonsils into the top of the spinal column. In a collection of magnetic resonance imagings (MRIs) from affected individuals and their family members, we measured correlations between ten cranial morphologies and estimated their heritability in these families. Correlations between bones delineating the PF and significant heritability of PF volume (0.955, P = 0.003) support the cramped PF theory and a genetic basis for this condition. In a collection of 23 families with 71 affected individuals, we performed a genome wide linkage screen of over 10,000 SNPs across the genome to identify regions of linkage to CMI. Two-point LOD scores on chromosome 15 reached 3.3 and multipoint scores in this region identified a 13 cM region with LOD scores over 1 (15q21.1-22.3). This region contains a biologically plausible gene for CMI, fibrillin-1, which is a major gene in Marfan syndrome and has been linked to Shprintzen-Goldberg syndrome, of which CMI is a distinguishing characteristic. Multipoint LOD scores on chromosome 9 maximized at 3.05, identifying a 40 cM region with LOD scores over 1 (9q21.33-33.1) and a tighter region with multipoint LOD scores over 2 that was only 8.5 cM. This linkage evidence supports a genetic role in Chiari malformation and justifies further exploration with fine mapping and investigation of candidate genes in these regions.

Multipoint Linkage Analysis with Many Multiallelic or Dense Diallelic Markers: Markov Chain–Monte Carlo Provides Practical Approaches for Genome Scans on General Pedigrees

Computations for genome scans need to adapt to the increasing use of dense diallelic markers as well as of full-chromosome multipoint linkage analysis with either diallelic or multiallelic markers. Whereas suitable exact-computation tools are available for use with small pedigrees, equivalent exact computation for larger pedigrees remains infeasible. Markov chain-Monte Carlo (MCMC)-based methods currently provide the only computationally practical option. To date, no systematic comparison of the performance of MCMC-based programs is available, nor have these programs been systematically evaluated for use with dense diallelic markers. Using simulated data, we evaluate the performance of two MCMC-based linkage-analysis programs--lm_markers from the MORGAN package and SimWalk2--under a variety of analysis conditions. Pedigrees consisted of 14, 52, or 98 individuals in 3, 5, or 6 generations, respectively, with increasing amounts of missing data in larger pedigrees. One hundred replicates of markers and trait data were simulated on a 100-cM chromosome, with up to 10 multiallelic and up to 200 diallelic markers used simultaneously for computation of multipoint LOD scores. Exact computation was available for comparison in most situations, and comparison with a perfectly informative marker or interprogram comparison was available in the remaining situations. Our results confirm the accuracy of both programs in multipoint analysis with multiallelic markers on pedigrees of varied sizes and missing-data patterns, but there are some computational differences. In contrast, for large numbers of dense diallelic markers, only the lm_markers program was able to provide accurate results within a computationally practical time. Thus, programs in the MORGAN package are the first available to provide a computationally practical option for accurate linkage analyses in genome scans with both large numbers of diallelic markers and large pedigrees.

Follow‐up mapping supports the evidence for linkage in the candidate region at 9q22 in the NIMH Alzheimer's disease Genetics Initiative cohort

Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD.

Mutations in DJ-1 are rare in familial Parkinson disease

Mutations in DJ-1 ( PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD.

A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3

Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant form of AI and mapped a novel locus to 8q24.3. A maximum multipoint LOD score of 7.5 was obtained at marker D8S2334 (146,101,309 bp). The disease locus lies in a 1.9 cM (2.1 Mb) region according to the Rutgers Combined Linkage-Physical map, between a VNTR marker (at 143,988,705 bp) and the telomere (146,274,826 bp). Ten candidate genes were identified based on gene ontology and microarray-facilitated gene selection using the expression of murine orthologues in dental tissue, and examined for the presence of a mutation. However, no causative mutation was identified.

Genome-wide scan identifies a susceptibility locus for familial primary cutaneous amyloidosis on chromosome 5p13.1-q11.2

Primary cutaneous amyloidosis (PCA) is a relatively common skin disorder in South America and Southeast Asia. Most cases of PCA are sporadic but familial aggregation has been reported from South America and Taiwan. The different susceptibility among ethnic groups suggests that genetic factors may play an important role in its pathogenesis. We aimed to perform a genome-wide scan by linkage analysis across 15 families with familial primary cutaneous amyloidosis (FPCA) to map the disease gene(s) for FPCA. A total of 15 FPCA families including 50 individuals affected with PCA were recruited. Throughout the 22 autosomes, 369 polymorphic microsatellite markers were used initially. Regions showing a LOD score > 1 identified in the initial scan were further analysed with additional markers. Two-point and multipoint linkage analysis were performed by using the LINKAGE program. Nonparametric linkage (NPL) analysis and reconstruction of haplotypes were performed with the GENEHUNTER program. A maximum two-point LOD score of 4.76 for the marker D5S1490 (theta = 0.10, alpha = 0.60) and a multipoint LOD score of 4.50 between D5S822 and D5S623 (alpha = 0.60) were obtained under the assumption of heterogeneity. A peak NPL score of 5.23 (P value = 0.000007) was found from D5S1490 to D5S2076. Further analysis focusing on two major families identifies a common haplotype shared by all affected individuals between D5S1490 and D5S623. To our knowledge, this is the first report of genome-wide analysis of a large number of FPCA pedigrees. Our study provides evidence for significant linkage to chromosome 5p13.1-q11.2 in a subset of FPCA families.

A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13

The authors investigated genetic factors contributing to restless legs syndrome (RLS) by performing a 10-cM genome-wide scan in a large French-Canadian pedigree. They detected an autosomal-dominant locus mapping to chromosome 20p13, with a maximum multipoint lod score of 3.86 at marker D20S849. This is the third reported autosomal-dominant locus for RLS and the first autosomal-dominant RLS locus in the French-Canadian population.

A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families

Tooth agenesis constitutes the most common anomaly of dental development in humans. In the majority of familial cases of hypodontia alone or in association with other anomalies, the mode of inheritance is autosomal dominant. In the present study, we have identified two distantly related consanguineous Pakistani kindreds with an autosomal recessive form of oligodontia with associated dental anomalies. Locus in this case has been mapped on chromosome 4p16.1-p16.3. The maximum two-point LOD score of 2.85 (theta=0.0) was obtained at markers D4S2925 and D4S2285. A maximum multipoint LOD score exceeding 4 was obtained at the same markers. Recombination events observed in affected individuals localized the disease locus between markers D4S412 and D4S2935, spanning a 9.24-cM region on chromosome 4p16.1-p16.3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and protein-protein interaction. The mutation, p. A219T, is the first recessive mutation identified in MSX1.

Characterization of a Susceptibility Locus for SLE, SLEB5, on Chromosome 4p14‐13

Systemic lupus erythematosus is a systemic autoimmune disorder of unknown aetiology but is most likely caused by an interaction between several genetic factors and the environment. In a previously published genome scan we presented linkage to a marker on chromosome 4p13 in Icelandic families. Fine mapping of the region has been performed using 10 multicase families from Iceland and the maximum two-point LOD score was given by marker D4S2974 (Z = 3.57, alpha = 1). Multipoint analyses of the markers in the region suggest a putative disease gene to be located between markers D4S405 and D4S2381. The maximum multipoint LOD score (Z = 3.76) was given for marker D4S2974 in combination with the novel repeat GT4C2. A family-specific haplotype was segregating with the disease in each of eight families although a founder haplotype could not be identified. Analysis of recombination events in the patients delimited the susceptibility locus to approximately 3 cM. The susceptibility locus identified probably contains a mutation that has been enriched in the Icelandic population but is less common in other populations. We also show that this region is not identical to a susceptibility locus for SLE located on 4p16 where we detect no linkage.

Evidence for a colorectal cancer susceptibility locus on chromosome 3q21-q24 from a high-density SNP genome-wide linkage scan

To identify a novel susceptibility gene for colorectal cancer (CRC), we conducted a genome-wide linkage analysis of 69 pedigrees segregating colorectal neoplasia in which involvement of known loci had been excluded, using a high-density single nucleotide polymorphism (SNP) array containing 10,204 markers. Multipoint linkage analyses were undertaken using both non-parametric (model-free) and parametric (model-based) methods. After the removal of SNPs in strong linkage disequilibrium, we obtained a maximum non-parametric linkage statistic of 3.40 (P=0.0003) at chromosomal region 3q21-q24. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=3.10, genome-wide P=0.038) with 62% of families linked to the locus. We provide evidence for a novel CRC susceptibility gene. Further studies are needed to confirm this localization and to evaluate the contribution of this locus to disease incidence.

Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies

Stature is a highly heritable trait under both polygenic and major gene control. We aimed to identify genetic regions linked to idiopathic short stature (ISS) in childhood, through a whole genome scan in 92 families each with two affected children with ISS, including constitutional delay of growth and puberty and familial short stature. Linkage analysis was performed for ISS, height and bone age retardation. Chromosome 12q11 showed significant evidence of linkage to ISS and height (maximum non-parametric multipoint LOD scores 3.18 and 2.31 at 55-58 cM, between D12S1301 and D12S1048), especially in sister-sister pairs (LOD score of 1.9 for ISS in 22 pairs). These traits were also linked to chromosomes 1q12 and 2q36. The region on chromosome 12q11 had previously shown significant linkage to adult stature in several genome scans and harbors the vitamin D receptor gene, which has been associated with variation in height. A single nucleotide polymorphism (SNP) (rs10735810, FokI), which leads to a functionally relevant alteration at the protein level, showed preferential transmission of the transcriptionally more active G-allele to affected children (P=0.04) and seems to be responsible for the observed linkage (P=0.05, GIST test). Bone age retardation showed moderate linkage to chromosomes 19p11-q11 and 7p14 (LOD scores 1.69 at 57 cM and 1.42 at 50 cM), but there was no clear overlap with linkage regions for stature. In conclusion, we identified significant linkage, which might be due to a functional SNP in the vitamin D receptor (VDR) gene and could be responsible for up to 34% of ISS cases in the population.

A Novel Human Sex-Determining Gene Linked to Xp11.21-11.23

The molecular basis for about 70-80% of 46,XY sex-reversed females remains unexplained, because they carry normal copies of the genes (SRY, SOX9, DAX1, DMRT, SF1, WT1) involved in sex determination pathway. The objective of this study is to map the chromosomal locus responsible for an unexplained sex-reversed phenotype. The study implemented a genome-wide scan using families with multiple sex-reversed individuals. The patients, along with the family members, were selected from different hospitals/reproductive centers. Sex-reversed individuals and their siblings and parents participated in the study. Identification of the chromosomal locus responsible for sex reversal in these families and sequence analysis of candidate genes were the main outcome measures. Parametric linkage analysis revealed a maximum two-point LOD score of 5.70 with marker DXS991 (Xp11.21) and 4.57 with marker DXS1039 (Xp11.23-Xp11.22), and a multipoint LOD score of 5.77 with marker DXS991 and 5.22 with marker DXS1039. The two markers (DXS991 and DXS1039) with highest LOD score span approximately 3.41 cM (75.79-79.2 cM) on the short arm of the X-chromosome. Our findings provide evidence for a major susceptibility locus for sex reversal/gonadal dysgenesis on the short arm of the X-chromosome (Xp11.21-11.23). Furthermore, molecular exploration of the expression of candidate genes in the embryonic gonad/gonadal ridge will help in the identification of the underlying gene for sex reversal.

Confirmation of linkage to chromosome 1q for spine bone mineral density in southern Chinese

Chromosome 1q has previously been linked to bone mineral density (BMD) variation in the general population in several genome-wide linkage studies in both humans and mouse model. The aim of present study is to replicate and fine map the QTL influencing BMD in chromosome 1q in southern Chinese. Twelve microsatellite markers were genotyped for a 57 cMu region in the chromosome 1q in 306 southern Chinese families with 1,459 subjects. Each of these families was ascertained through a proband with BMD Z-scores less than -1.3 at the hip or spine. BMD (g/cm2) at the L1-4 lumbar spine, femoral neck (FN), trochanter and total hip was measured by dual-energy X-ray absortiometry. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software. Four markers (D1S2878, D1S196, D1S452, and D1S218) achieved a LOD score greater than 1.0 with spine BMD, with the maximum multipoint LOD score of 2.36 at the marker D1S196. We did not detect a LOD score greater than 1.0 for BMD at the FN, trochanter, or total hip in multipoint linkage analyses. Our results present the first evidence for the presence of an osteoporosis susceptibility gene on chromosome 1q in non-Caucasian subjects. Further analyses of candidate genes are warranted to identify QTL genes and variants underlying the variations of BMD in this region.