Multipoint Nonparametric Linkage Research Articles

Mapping of developmental dysplasia of the hip to two novel regions at 8q23-q24 and 12p12.

Developmental dysplasia of the hip (DDH), previously known as congenital hip dislocation, is a frequently disabling condition characterized by premature arthritis later in life. Genetic factors play a key role in the aetiology of DDH. In the present study, a genome-wide linkage scan with the Affymetrix 10K GeneChip was performed on a four-generation Chinese family, which included 19 healthy members and 5 patients. Parametric and non-parametric multipoint linkage analyses were carried out with Genespring GT v.2.0 software, and the logarithm of odds (LOD) score and nonparametric linkage (NPL) score were calculated. Parametric linkage analysis was performed, assuming an autosomal recessive trait with full penetrance and Affymetrix 'Asian' allele frequencies. The strongest evidence for linkage was found on chromosome 8q23-24, with a peak LOD score of 2.658 (θ=0), covering 2.377 Mb from single nucleotide polymorphisms (SNPs) rs724717 to rs720132. This interval included nine additional successive SNPs: rs1566071, rs1902121, rs756404, rs702768, rs777813, rs2033995, rs147959, rs2884367 and rs1898287. The same region also yielded the highest NPL score of 2.883 (P=0.0156) from the non-parametric multipoint linkage analysis. Additionally, the second highest NPL score of 2.727 (P=0.0156) and LOD score of 2.528 (θ=0) were obtained on chromosome 12p12 for three consecutive markers (rs1919980, rs763853 and rs725124). This region overlapped a narrow distance of 0.642 Mb. Notably, in addition to these two regions; no significant linkage was identified for other chromosomal regions (with LOD and NPL scores >2.0). For the first time, at least for this pedigree, the evidence in the present study showed that DDH is mapped to two novel regions at 8q23-q24 and 12p12.

Evidence of linkage to chromosome 5p13.2-q11.1 in a large inbred family with genetic generalized epilepsy.

The clinical genetics of genetic generalized epilepsy suggests complex inheritance; large pedigrees, with multiple affected individuals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks; in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic-clonic seizures were seen in 11. One individual had generalized tonic-clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected individual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2-q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein-coding variants within the highly significant linkage region that includes HCN1 as a promising candidate.

Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations. In all, 44 individuals with Primary Biliary Cholangitis and 61 unaffected relatives from 32 First Nations families participated. Family history and co-morbidities were documented. Medical records were reviewed and available biopsies were re-reviewed by our team pathologist. Genotyping was performed on DNA from 36 affected persons and 27 unaffected relatives using the Affymetrix Human Mapping 500K Array Set. MERLIN software was used to carry out multipoint parametric and nonparametric linkage analysis. Candidate genes were identified and entered into InnateDB and KEGG software to identify potential pathways affecting pathogenesis. In all, 34% of families were multiplex. Fifty per cent of cases and 33% of unaffected relatives reported other autoimmune disease. Three genomic regions (9q21, 17p13 and 19p13) produced LOD scores of 2.3 or greater suggestive of linkage, but no single linkage peak reached statistical significance. Candidate genes identified in the three regions suggested involvement of IL17, NFκB, IL6, JAK-STAT, IFNγ and TGFβ immune signalling pathways. Specifically, four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in these pathways that may influence Primary Biliary Cholangitis pathogenesis. Our whole genome linkage study results reflect the multifactorial nature of Primary Biliary Cholangitis, support previous studies suggesting signalling pathway involvement and identify new candidate genes for consideration.

Mutation analysis of a Chinese pedigree of Leber hereditary optic neuropathy with only male patients

Background Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by a bilateral acute or subacute painless central visual loss in young adults, predominately in males.So far no one theory can completely explain all clinical manifestations of LHON. Objective This study was to investigate whether there is a linkage between X-chromosomal and mitochondrial mutation in the inheritance of a Chinese LHON pedigree with only male patients. Methods This study was approved by Ethic Committee of Affiliated First Hospital of Zhengzhou University and followed by Declaration of Helsinki.A Chinese LHON pedigree was included in Anyang city from January 2008 to August 2016.Periphery blood of 5-10 ml was collected from 4 sufferers, 13 maternal members and 10 non-maternal members for DNA extraction and PCR sequencing.The gene scanning and genotyping analysis were performed by ABI-PRISM 3100 genetic analyzer and Genotyper 3.7 software, and linkage analysis was carried out with Linkage software for the calculation of logarithm of odds (LOD). Mitochondrial DNA (mtDNA) sequence, fluorescence-based Genescan for X- chromosomal sequence were analyzed in the propositus and haplotype was evaluated. Results A total of 5 generations and 71 families were included in the pedigree, with 6 male sufferers, 30 maternal members and 41 non-maternal members.The visual acuity was ≤0.10, and the central visual field defection, the optic nerve flushing was found in the acute phase, different levels of the optic nerve fibers atrophy were found in the chronic phase; visual evoked potential (VEP) amplitude was low and peak latency were found in the male patients, and no any ocular abnormality was seen in the maternal members, meeting a maternally inherited characteristics, with the penetrance of 20%.The three primary mutations were not been found in this family by PCR sequencing.mtDNA sequencing appeared 31 variation of loci in the proband, including a known G3635A mutation, as well as an unknown ND5 A12340G missense mutation and ND4 T11809C synonymous mutation as well as 28 polymorphism of locus, and the proband was mitochondrial haplotype F1.The maternal families were mutation carriers of G3635A and A12340G loci, while the same mutation was not found in the normal family members and 107 controls.The maximum two point parametric LOD score was 1.46(θ=0.0) for marker DXS1060, located at Xp22.3, and the two-point and multipoint non-parametric linkage analysis were significant (all at P>0.05). Conclusions The ND5 A12340G and ND1 G3635A mutations coexist in this LHON family, and the ND5 A12340G mutation is a newly reported mutation.There is no evidence for an X-linked modifiers loci in this Chinese LHON family. Key words: Leber hereditary optic neuropathy/genetics; X-linked modifiers locus; Microsatellite marker; Parametric linkage analysis; Non-parametric linkage analysis

Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13.

A genome-wide scan was conducted for the levels of total immunoglobulin G (IgG) and IgG subclasses directed against Plasmodium falciparum antigens in an urban population living in Burkina Faso. Non-parametric multipoint linkage analysis provided three chromosomal regions with genome-wide significant evidence (logarithm of the odds (LOD) score >3.6), and five chromosomal regions with genome-wide suggestive evidence (LOD score >2.2). IgG3 levels were significantly linked to chromosomes 8p22-p21 and 20q13, whereas IgG4 levels were significantly linked to chromosome 9q34. In addition, we detected suggestive linkage of IgG1 levels to chromosomes 18p11-q12 and 18q12-q21, IgG4 levels to chromosomes 1p31 and 12q24 and IgG levels to chromosome 6p24-p21. Moreover, we genotyped genetic markers located within the regions of interest in a rural population living in Burkina Faso. We detected genome-wide significant and suggestive linkage results when combining the two study populations for chromosomes 1p31, 6p24-p21, 8p22-p21, 9q34, 12q24 and 20q13. Because high anti-parasite IgG3 and low anti-parasite IgG4 levels were associated with malaria resistance, the chromosomal regions linked to IgG3 and IgG4 levels are of special interest. Although the results should be confirmed in an independent population, they may provide new insights in understanding both the genetic control of IgG production and malaria resistance.

Genetic susceptibility to non-necrotizing erysipelas/cellulitis.

BackgroundBacterial non-necrotizing erysipelas and cellulitis are often recurring, diffusely spreading infections of the skin and subcutaneous tissues caused most commonly by streptococci. Host genetic factors influence infection susceptibility but no extensive studies on the genetic determinants of human erysipelas exist.MethodsWe performed genome-wide linkage with the 10,000 variant Human Mapping Array (HMA10K) array on 52 Finnish families with multiple erysipelas cases followed by microsatellite fine mapping of suggestive linkage peaks. A scan with the HMA250K array was subsequently performed with a subset of cases and controls.ResultsSignificant linkage was found at 9q34 (nonparametric multipoint linkage score (NPLall) 3.84, p = 0.026), which is syntenic to a quantitative trait locus for susceptibility to group A streptococci infections on chromosome 2 in mouse. Sequencing of candidate genes in the 9q34 region did not conclusively associate any to erysipelas/cellulitis susceptibility. Suggestive linkage (NPLall>3.0) was found at three loci: 3q22-24, 21q22, and 22q13. A subsequent denser genome scan with the HMA250K array supported the 3q22 locus, in which several SNPs in the promoter of AGTR1 (Angiotensin II receptor type I) suggestively associated with erysipelas/cellulitis susceptibility.ConclusionsSpecific host genetic factors may cause erysipelas/cellulitis susceptibility in humans.

HELLP babies link a novel lincRNA to the trophoblast cell cycle

The HELLP syndrome is a pregnancy-associated disease inducing hemolysis, elevated liver enzymes, and low platelets in the mother. Although the HELLP symptoms occur in the third trimester in the mother, the origin of the disease can be found in the first trimester fetal placenta. A locus for the HELLP syndrome is present on chromosome 12q23 near PAH. Here, by multipoint nonparametric linkage, pedigree structure allele sharing, and haplotype association analysis of affected sisters and cousins, we demonstrate that the HELLP locus is in an intergenic region on 12q23.2 between PMCH and IGF1. We identified a novel long intergenic noncoding RNA (lincRNA) transcript of 205,012 bases with (peri)nuclear expression in the extravillous trophoblast using strand-specific RT-PCR complemented with RACE and FISH. siRNA-mediated knockdown followed by RNA-sequencing, revealed that the HELLP lincRNA activated a large set of genes that are involved in the cell cycle. Furthermore, blocking potential mutation sites identified in HELLP families decreased the invasion capacity of extravillous trophoblasts. This is the first large noncoding gene to be linked to a Mendelian disorder with autosomal-recessive inheritance.

Genome-Wide Linkage and Association Analysis Identifies Major Gene Loci for Guttural Pouch Tympany in Arabian and German Warmblood Horses

Equine guttural pouch tympany (GPT) is a hereditary condition affecting foals in their first months of life. Complex segregation analyses in Arabian and German warmblood horses showed the involvement of a major gene as very likely. Genome-wide linkage and association analyses including a high density marker set of single nucleotide polymorphisms (SNPs) were performed to map the genomic region harbouring the potential major gene for GPT. A total of 85 Arabian and 373 German warmblood horses were genotyped on the Illumina equine SNP50 beadchip. Non-parametric multipoint linkage analyses showed genome-wide significance on horse chromosomes (ECA) 3 for German warmblood at 16–26 Mb and 34–55 Mb and for Arabian on ECA15 at 64–65 Mb. Genome-wide association analyses confirmed the linked regions for both breeds. In Arabian, genome-wide association was detected at 64 Mb within the region with the highest linkage peak on ECA15. For German warmblood, signals for genome-wide association were close to the peak region of linkage at 52 Mb on ECA3. The odds ratio for the SNP with the highest genome-wide association was 0.12 for the Arabian. In conclusion, the refinement of the regions with the Illumina equine SNP50 beadchip is an important step to unravel the responsible mutations for GPT.

Chromosome 2p14 is linked to susceptibility to leprosy.

BackgroundA genetic component to the etiology of leprosy is well recognized but the mechanism of inheritance and the genes involved are yet to be fully established.MethodologyA genome-wide single nucleotide polymorphism (SNP) based linkage analysis was carried out using 23 pedigrees, each with 3 to 7 family members affected by leprosy. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1.Principal FindingsGenome-wide significant evidence for linkage was identified on chromosome 2p14 with a heterogeneity logarithm of odds (HLOD) score of 3.51 (rs1106577) under a recessive model of inheritance, while suggestive evidence was identified on chr.4q22 (HLOD 2.92, rs1349350, dominant model), chr. 8q24 (HLOD 2.74, rs1618523, recessive model) and chr.16q24 (HLOD 1.93, rs276990 dominant model). Our study also provided moderate evidence for a linkage locus on chromosome 6q24–26 by non-parametric linkage analysis (rs6570858, LOD 1.54, p = 0.004), overlapping a previously reported linkage region on chromosome 6q25–26.ConclusionA genome-wide linkage analysis has identified a new linkage locus on chromosome 2p14 for leprosy in Pedigrees from China.

Association of a single nucleotide polymorphism in pregnancy-associated plasma protein-A2 with developmental dysplasia of the hip: a case–control study

Developmental dysplasia of the hip (DDH), previously known as congenital hip dislocation, is a frequently disabling condition characterized by premature arthritis in later life. Genetic influence on DDH has been long known, but is still poorly understood. Previously, we have performed a genome-wide linkage scan with Affymetrix 10K genechip for a four-generation Chinese family, which included 19 healthy members and five patients with DDH. Parametric and nonparametric multipoint linkage analyses were carried out with Genespring GT v.2.0 software, and the logarithm of odds (LOD) score and nonparametric linkage (NPL) score were calculated. For parametric linkage analysis, an assuming autosomal recessive trait was used with full penetrance, and Affymetrix "Asian" allele frequencies. The NPL score of 2.698 (P=0.0156) and LOD score of 2.119 (θ=0) were obtained on chromosome 1q25.2a for one marker (rs726252). The single nucleotide polymorphism (SNP) rs726252 locates in the region of fifth intron of pregnancy-associated plasma protein-A2 (PAPPA2). Although neither LOD nor NPL scores of rs726252 has exceeded 3.0, several researches have demonstrated that PAPPA2 have important consequences for the development of the fetus and normal postnatal growth. To further evaluate this possible association, in the present study, we examined the genetic association of rs726252 in PAPPA2 gene with sporadic DDH in Han Chinese population using case-control study, including 310 patients with sporadic DDH and 487 control subjects, and found a significant association between PAPPA2 and DDH.

Genome‐wide linkage analysis of Swedish families to identify putative susceptibility loci for cutaneous malignant melanoma

Cutaneous malignant melanoma is a clinically and genetically heterogeneous disorder which is caused by an interaction between hereditary and environmental factors. In Sweden, a small portion of the inherited susceptibility is explained by the presence of germline mutations in the tumor suppressor gene CDKN2A. But still, the genetic background of melanoma susceptibility is largely unknown. Here, we conducted a genome-wide linkage scan on melanoma-prone families using high-density single-nucleotide polymorphisms (SNPs) arrays to identify novel melanoma susceptibility genes. We investigated 35 families of Swedish origin without CDKN2A mutations. Nonparametric and parametric multipoint linkage analyses were performed. After removal of SNPs in strong linkage disequilibrium, the strongest evidence of linkage was detected on chromosome 17p11-12 (logarithm (base 10) of odds (LOD) scores of 2.76) using parametric linkage analysis assuming a dominant trait with full penetrance. Analyses were also performed on a subset of families with low age at diagnosis (mean age ≤ 47 years), to obtain a more homogenous subset. This subgroup analysis based on 22 families yielded suggestive evidence of linkage to the chromosomal regions 11p12-p11 and 18q22 (multipoint LOD scores of 2.10 and 2.02, respectively). Also, the 17p region that was detected in the complete family set showed suggestive linkage in this cohort (multipoint LOD scores of 2.01). Our data suggest that these chromosomal regions, 17p12-p11 in particular as it was present in both analyses, may harbor genes involved in the susceptibility of malignant melanoma in the Swedish population.

Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

BackgroundDiabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21–q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.Methods and ResultsWe performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPLpairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets.ConclusionsThis study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21–q25 and 19q13.

Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study.

In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using Sall statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.

Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia

To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. 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. 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. 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.

The Identification of a Novel Locus for Mandibular Prognathism in the Han Chinese Population

Mandibular prognathism is a common dentofacial phenotype with a substantial genetic component; however, few susceptibility loci have been mapped. Ethnicity is a risk factor for mandibular prognathism, and a relatively high prevalence is observed in Asian populations. The hypothesis of this study suggested that a specific locus for mandibular prognathism exists in the Han Chinese population. So, the authors studied a Han Chinese pedigree in which mandibular prognathism was inherited (11 affected, 10 unaffected) in an autosomal dominant pattern. A genomewide linkage scan was performed with the Illumina Linkage-12 DNA Analysis Kit. Multipoint parametric and nonparametric linkage analyses were performed with MERLIN 1.01. A susceptibility locus was identified on chromosome 14q24.3-31.2, with a nonparametric linkage score of 11.341 (empirical P = .020) and a logarithm of the odds score of 2.032 (empirical P = .008). Haplotype analysis refined the candidate locus to a 10.62-cM interval (72.42 to 83.14 cM; 74.57 to 84.66 Mb) between rs1468507 and rs7141857. Within this interval, the candidate functional genes are TGFB3 and LTBP2. In conclusion, the authors detected a suggestive linkage for mandibular prognathism in a Han Chinese pedigree, and this finding can be combined with previous studies to further understand the genetic basis of mandibular prognathism.

Genome-wide and Interaction Linkage Scan for Nonsyndromic Cleft Lip with or without Cleft Palate in Two Multiplex Families in Shenyang, China

To identify the loci involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Northern Chinese people in Shenyang by using genomewide and interaction linkage scan. Two multiplex families in Shenyang from North China were ascertained through probands with NSCL/P. Blood of every member was drawn for DNA extraction and analysis. Genotypes were available for 382 autosomal short tandem repeat (STR) markers from the ABI Prism Linkage Mapping Set version 2.5. Linkage between markers and NSCL/P was assessed by 2-point parametric LOD scores, multipoint-heterogeneity parametric LOD scores (HLODs), and multipoint nonparametric linkage score (NPL). The initial scan suggested linkage on Chromosomes 1, 2, and 15. In subsequent fine mapping, 1q32-q42 showed a maximum multipoint LOD score of 1.9(empirical P=0.013) and an NPL score of 2.35 (empirical P=0.053). For 2p24-p25, the multipoint NPL increased to 2.94 (empirical P=0.007). 2-locus interaction analysis obtained a maximum NPL score of 3.73 (P=0.00078) and a maximum LOD score of 3 for Chromosome 1 (at 221 cM) and Chromosome 2 (at 29 cM). Both parametric and nonparametric linkage scores greatly increased over the initial linkage scores on 1q32-q42, suggesting a susceptibility locus in this region. Nonparametric linkage gave a strong evidence for a candidate region on chromosome 2p24-p25. The superiority of 2-locus linkage scores compared to single-locus scores gave additional evidence for linkage on 1q32-q42 and 2p24-p25, and suggested that certain genes in the two regions may contribute to NCSL/P risks with interaction.

Genome Scan for Locus Involved in Mandibular Prognathism in Pedigrees from China

BackgroundIt is well known that genetic components play an important role in the etiology of mandibular prognathism, but few susceptibility loci have been mapped.MethodologyIn order to identify linkage regions for mandibular prognathism, we analyzed two Chinese pedigrees with 6,090 genome-wide single-nucleotide polymorphism (SNP) markers from Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Multipoint parametric and non-parametric (model-free) linkage analyses were used for the pedigrees.Principal FindingThe most statistically significant linkage results were with markers on chromosome 4 (LOD = 3.166 and NPL = 3.65 with rs 875864, 4p16.1, 8.38 cM). Candidate genes within the 4p16.1 include EVC, EVC2.ConclusionWe detected a novel suggestive linkage locus for mandibular prognathism in two Chinese pedigrees, and this linkage region provides target for susceptibility gene identification, a process that will provide important insights into the molecular and cellular basis of mandibular prognathism.

Linkage analysis of Tourette syndrome in a large utah pedigree

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and phonic tics. The heritability of TS has been well established, yet there is a lack of consensus in genome-wide linkage studies. The purpose of this study was to conduct a genome-wide linkage analysis on a unique, large, high-risk TS Utah pedigree. We examined a qualitative trait (TS1) where cases had a definitive diagnosis of TS as observed by a clinical interviewer (n = 66) and a quantitative phenotype based on the total Yale global motor and phonic tic severity scores (n = 102). Both parametric and non-parametric multipoint linkage analyses based on MCMC methods were performed using a 10 cM spaced micro-satellite autosomal marker set. Two regions of interest were identified under affecteds-only recessive models; a LOD score of 3.3 on chromosome 1p for Yale tic severity and a LOD score of 3.1 on chromosome 3p for the TS1 phenotype. Twenty-seven individuals shared linked segregating haplotypes for the 1p region. They had significantly higher Yale tic phonic scores than non-sharers (P = 0.01). There were 46 haplotype sharers on chromosome 3p with significantly higher percentage of females among these individuals compared to the non-sharers (P = 0.03). The significant linkage peaks on chromosomes 1p and 3p are in new areas of the genome for TS, and replication of these findings is necessary.

Two-Dimensional Genome Scan Identifies Multiple Genetic Interactions in Bipolar Affective Disorder

Bipolar disorder is a highly heritable psychiatric condition, the etiology of which remains largely unknown despite extensive efforts to identify susceptibility genes. Interactions between genes of small individual effect could partially explain the difficulties of traditional one-dimensional approaches to identify genetic risk factors. A nonparametric linkage (NPL) analysis of 65 Australian extended pedigrees containing 643 genotyped individuals (of whom 40% were diagnosed with affective disorder) was conducted. Chromosome-by-chromosome correlation analysis of family-specific NPL scores was conducted to detect evidence of genetic interaction. Interaction-specific multipoint NPL and permutation analysis was used to assess linkage interdependence, using family weights derived from the alternative interacting chromosome. Finally, a single nucleotide analysis of each interaction region was conducted using the publicly available genome-wide association, datasets (2933 cases, 2534 controls). Significant NPL peaks were detected on chromosomes 2q24-33, 7q21-31, and 17q11-25 (Z = 3.12, 3.01, and 2.95 respectively), with four additional suggestive peaks identified. Four robust interchromosomal interaction clusters exceeding Bonferroni correction at alpha = .05 (uncorrected p < 5.38e-07) were detected on 11q23-25-2p15-12, 4q32-35-1p36, 12q23-24-4p16-15, and 20q13-9q21-22. This linkage interdependence was determined significant after permutation analysis (p = .002-.0002). A suggestive interaction was observed in the combined data on 2p14-11q23 (uncorrected p = 5.76E-10, Bonferroni corrected p = .068). This study indicates a complex interplay between multiple loci underlying bipolar disorder susceptibility, and highlights the continuing usefulness of extended pedigrees in complex genetics. The challenge lies in the identification of specific gene interactions and their biological validation.

Use of supplementary phenotype to identify additional rheumatoid arthritis loci in a linkage analysis of 342 UK affected sibling pair families

BackgroundAlthough rheumatoid arthritis has been shown to have moderately strong genetic component, both linked loci identified in linkage analyses and susceptibility variants from association studies are short of adequately accounting for a comprehensive catalogue of the molecular factors underlying this complex disease. The objective of this study was to use supplementary phenotype based on cumulative hazard of rheumatoid arthritis to identify linkage evidence for new and additional rheumatoid arthritis loci in a genome-wide linkage analysis of 342 affected sibling pair families from the United Kingdom.MethodsUsing proportional hazards model, we estimated cumulative hazard of rheumatoid arthritis and then used it as a quantitative trait in a non-parametric multipoint variance component linkage analysis with 353 microsatellite markers distributed across the 22 autosomal chromosomes.ResultsWe identified 3 new loci with genome-wide suggestive linkage evidence for rheumatoid arthritis on 9q21.13, 15p11.1 and 20q13.33. Our results also confirmed previously reported linkage evidence in the HLA-DRB1 region on chromosome 6 and on locus 1q32.1.ConclusionThis study demonstrates the potential for information gain through the use of supplementary phenotypes in genetic study of complex diseases to identify new and additional potential linked loci that are not detected by linkage analysis of traditional phenotypes; and our results provide further evidence of the involvement of multiple loci in the genetic aetiology of rheumatoid arthritis.