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1.  Recessive Developmental Delay, Small Stature, Microcephaly and Brain Calcifications with Locus on Chromosome 2 
Two interrelated Omani families are described with eight children manifesting a genetic disorder with widespread brain calcifications. Brain imaging showed extensive scattered calcifications of basal ganglia and cortex, suggesting possible Aicardi-Goutiéres syndrome (AGS) or Coats’ Plus syndrome. However, the clinical features in the present families diverge substantially from these two conditions. Growth delay, mild developmental delay and poor school performance were present in all affected individuals, but progressive deterioration of neurological function was not apparent, nor were there significant cortical whitematter disease or retinopathy. Genome-wide linkage and fine-mapping analyses of the extended family members and affected individuals indicate a genetic locus for this disorder on Chromosome 2 with a LOD score of 6.17. The Chromosome 2 locus is novel and the clinical presentation displays features distinguishing the condition from either Coats’ or AGS, making this a new variant or possibly a new disorder of inherited brain calcification.
PMCID: PMC2800951  PMID: 19161147
brain calcifications; hydrocephalus; autosomal recessive inheritance; microcephaly; developmental delay; Aicardi-Goutiéres syndrome; Coats’ Plus syndrome
2.  The Genetics of Reading Disability in an Often Excluded Sample: Novel Loci Suggested for Reading Disability in Rolandic Epilepsy 
PLoS ONE  2012;7(7):e40696.
Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating “pure” dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE.
We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus.
In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation.
Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in “pure” dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.
PMCID: PMC3399896  PMID: 22815793
3.  Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9 
BMC Neurology  2008;8:32.
Frontotemporal 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.
Clinical 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.
Neuropathological 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.
Our 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.
PMCID: PMC2553097  PMID: 18755042
4.  Genome‐wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica 
Thorax  2006;62(3):224-230.
Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma‐related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans.
Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV1) and FEV1/ forced vital capacity (FVC; both pre‐bronchodilator and post‐bronchodilator) and BDR were performed in these eight families (pre‐bronchodilator spirometry, n = 640; post‐bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking.
Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV1 (post‐bronchodilator) was found on chromosome 7q34–35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV1/FVC (pre‐bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near‐significant evidence of linkage to FEV1/FVC (post‐bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV1 on chromosomes 3q (pre‐bronchodilator, LOD = 2.74) and 4q (post‐bronchodilator, LOD = 2.66).
In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV1 on chromosome 7q34–35. In these families, FEV1/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
PMCID: PMC2117166  PMID: 17099076
5.  Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families 
A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers.
GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene.
The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer.
Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
PMCID: PMC2949638  PMID: 20637093
6.  Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi–Goutières syndrome 
eLife  null;4:e08007.
Aicardi–Goutières syndrome (AGS) is a severe childhood inflammatory disorder that shows clinical and genetic overlap with systemic lupus erythematosus (SLE). AGS is thought to arise from the accumulation of incompletely metabolized endogenous nucleic acid species owing to mutations in nucleic acid-degrading enzymes TREX1 (AGS1), RNase H2 (AGS2, 3 and 4), and SAMHD1 (AGS5). However, the identity and source of such immunogenic nucleic acid species remain undefined. Using genome-wide approaches, we show that fibroblasts from AGS patients with AGS1-5 mutations are burdened by excessive loads of RNA:DNA hybrids. Using MethylC-seq, we show that AGS fibroblasts display pronounced and global loss of DNA methylation and demonstrate that AGS-specific RNA:DNA hybrids often occur within DNA hypomethylated regions. Altogether, our data suggest that RNA:DNA hybrids may represent a common immunogenic form of nucleic acids in AGS and provide the first evidence of epigenetic perturbations in AGS, furthering the links between AGS and SLE.
eLife digest
The immune system protects the body from attack by bacteria, viruses, and other microbes. A key feature of this system is the ability to discriminate between the body's own cells and potential foreign invaders. Occasionally, this process can go wrong and the immune system starts attacking its own tissues, which can lead to arthritis, diabetes, lupus, and other ‘autoimmune’ diseases.
Aicardi–Goutières syndrome (AGS) is an autoimmune disease that leads to severe mental and physical symptoms. Recent research has revealed that the disease is caused by mutations in genes that make enzymes called nucleases. In healthy people, these enzymes destroy DNA molecules and other nucleic acids. In AGS patients, the failure of the nucleases to act is thought to lead to the accumulation of unwanted DNA and RNA molecules. These molecules, in turn, are thought to be mistakenly identified by the immune system as ‘foreign’ and to cause an autoimmune response. However, it is not clear how this works.
Here, Lim et al. studied skin cells called fibroblasts from patients with Aicardi–Goutières syndrome. The experiments found that the patients' cells had excessive numbers of RNA molecules binding to sections of matching DNA. These unusual DNA–RNA ‘hybrids’ accumulated in regions of the genome that do not contain many genes, perhaps as a result of breaks in the DNA. It is possible that they may mimic nucleic acids from viruses and could trigger an autoimmune response.
In healthy individuals, small ‘methyl’ groups are often attached to DNA in a process known as DNA methylation. This serves to maintain the stability of the genome and controls the activity of genes. Unexpectedly, Lim et al. found that the DNA in AGS patients had far fewer methyl groups, especially in areas where the DNA–RNA hybrids had accumulated. This may lead to genome destabilization, alterations in gene activity, and may mean that the DNA in these regions may be mistaken for foreign DNA by the immune system.
Altogether, Lim et al.'s findings suggest that Aicardi–Goutières syndrome may be caused by immune responses triggered by the accumulation of RNA–DNA hybrids and lower levels of DNA methylation. These findings may aid the development of new therapies to treat Aicardi–Goutières syndrome, lupus, and other similar diseases.
PMCID: PMC4528086  PMID: 26182405
Aicardi–Goutières syndrome; DNA methylation; RNA:DNA hybrids; RNase H2; human
7.  Genome-Wide Linkage Scan in Gullah-Speaking African American Families With Type 2 Diabetes 
Diabetes  2009;58(1):260-267.
OBJECTIVE—The Gullah-speaking African American population from the Sea Islands of South Carolina is characterized by a low degree of European admixture and high rates of type 2 diabetes and diabetic complications. Affected relative pairs with type 2 diabetes were recruited through the Sea Islands Genetic African American Registry (Project SuGAR).
RESEARCH DESIGN AND METHODS—We conducted a genome-wide linkage scan, genotyping 5,974 single nucleotide polymorphisms in 471 affected subjects and 50 unaffected relatives from 197 pedigrees. Data were analyzed using a multipoint engine for rapid likelihood inference and ordered subsets analyses (OSAs) for age at type 2 diabetes diagnosis, waist circumference, waist-to-hip ratio, and BMI. We searched for heterogeneity and interactions using a conditional logistic regression likelihood approach.
RESULTS—Linkage peaks on chromosome 14 at 123–124 cM were detected for type 2 diabetes (logarithm of odds [LOD] 2.10) and for the subset with later age at type 2 diabetes diagnosis (maximum LOD 4.05). Two linkage peaks on chromosome 7 were detected at 44–45 cM for type 2 diabetes (LOD 1.18) and at 78 cM for type 2 diabetes (LOD 1.64) and the subset with earlier age at type 2 diabetes diagnosis (maximum LOD 3.93). The chromosome 14 locus and a peak on 7p at 29.5 cM were identified as important in the multilocus model. Other regions that provided modest evidence for linkage included chromosome 1 at 167.5 cM (LOD 1.51) and chromosome 3 at 121.0 cM (LOD 1.61).
CONCLUSIONS—This study revealed a novel type 2 diabetes locus in an African American population on 14q that appears to reduce age of disease onset and confirmed two loci on chromosome 7.
PMCID: PMC2606883  PMID: 18835935
8.  Prolonged Signal-Averaged P-wave Duration as an Intermediate Phenotype for Familial Atrial Fibrillation 
To perform a genome-wide linkage analysis in a large atrial fibrillation (AF) kindred using AF and abnormally prolonged signal-averaged (SA) P-wave duration as the phenotype.
While inherited forms of AF exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. The identification of intermediate or endophenotypes may accelerate this effort.
A genome-wide linkage analysis was performed in a 4-generation AF kindred of 27 individuals, 8 with AF documented by ECG. The analysis was performed using AF as the phenotype, and repeated using an abnormally prolonged SA P-wave duration as the phenotype.
Linkage analysis and fine mapping generated a maximum multipoint logarithm of the odds (LOD) score of 3.0 at chromosome 5p15 between markers D5S406 and D5S635. Importantly, eight heterozygous carriers had a prolonged SA P-wave (203±21 msec) compared with 17 non-carriers (116±12 msec, P<0.00001). Using prolonged SA P-wave (conventionally defined as >155 msec) as an endophenotype, a maximum LOD score of 3.6 was obtained in the same region of chromosome 5p15, a span of 5.75 cM.
In a large AF kindred, we have identified a novel AF locus on chromosome 5p15 and demonstrated that affected individuals with AF and mutation carriers can be identified by a prolonged SA P-wave duration. Importantly, identification of an endophenotype in this kindred not only aided ascertainment of additional family members but also increased the LOD score providing increased support for linkage at this locus. Identification of the causal gene, mapped to chromosome 5p15, will advance our understanding of the molecular basis of AF.
Condensed Abstract
While inherited forms of atrial fibrillation (AF) exist, phenotypic complexity has limited efforts to ascertain mutation carriers and identify causal genes. In a large AF kindred, we have identified a new AF locus on chromosome 5p15 and demonstrated that that affected individuals with AF and mutation carriers can be identified by a prolonged signal-averaged (SA) P-wave duration. Identification of an intermediate or endophenotype not only aided ascertainment of additional family members but also increased the LOD score and will accelerate identification of the causal gene in this kindred.
PMCID: PMC2279191  PMID: 18342226
atrial fibrillation; familial; genetics; P-wave duration; endophenotype
9.  A genome wide linkage analysis in Swedish families with hereditary non‐familial adenomatous polyposis/non‐hereditary non‐polyposis colorectal cancer 
Gut  2006;55(3):362-366.
Background and aim
Known colorectal cancer syndromes, such as familial adenomatous polyposis and hereditary non‐polyposis colorectal cancer, have been identified in only a small proportion of cases with a family history of disease. In an attempt to identify loci harbouring novel predisposing genes, we have performed a genome wide linkage analysis in 18 colorectal cancer families recruited from the Department of Clinical Genetics at Karolinska Hospital, Sweden.
Multipoint parametric and non‐parametric linkage analyses were performed using two affected status criteria, stringent and less stringent. Parametric analysis was performed under the assumption of locus homogeneity and locus heterogeneity.
The initial scan performed using the less stringent affected status criteria revealed regions of interest on chromosome 11 (marker D11S1314: heterogeneity logarithm of odds (HLOD) score 1.96, non‐parametric LOD (NPL) score 1.28; and marker D11S908: HLOD score 2.10, NPL score 2.16) and chromosome 14 (marker D14S258: HLOD score 2.61, NPL score 2.88). Using the stringent affected status criteria, a locus on chromosome 22 was suggested in the parametric analysis (marker D22S315: HLOD score 1.26). After finemapping of the regions on chromosomes 11 and 14, HLOD and NPL scores were reduced but still within the range of suggestive linkage. Haplotype analysis revealed overlapping regions between D11S987 and D11S4207 (proximal region), D11S4120 and D11S4090 (distal region), on chromosome 11, and between D14S1038 and D14S1069 on chromosome 14.
Our study provides evidence of genetic heterogeneity among Swedish colorectal cancer families. Three novel regions were suggested to be of interest in a proportion of families analysed. Further studies are needed to confirm this result.
PMCID: PMC1856098  PMID: 16150854
linkage analysis; hereditary non‐polyposis colorectal cancer; familial adenomatous polyposis; colorectal cancer; chromosome 11; chromosome 14; chromosome 22
10.  Chromosome 2p14 Is Linked to Susceptibility to Leprosy 
PLoS ONE  2012;7(1):e29747.
A 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.
A 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 Findings
Genome-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.
A genome-wide linkage analysis has identified a new linkage locus on chromosome 2p14 for leprosy in Pedigrees from China.
PMCID: PMC3253103  PMID: 22238647
11.  The mapping of DFNB62, a new locus for autosomal recessive non-syndromic hearing impairment, to chromosome 12p13.2-p11.23 
Clinical genetics  2006;69(5):429-433.
Autosomal recessive non-syndromic hearing impairment (ARNSHI) is the most common form of prelingual inherited hearing impairment (HI). Here is described the mapping of a novel ARNSHI locus in a consanguineous Pakistani family with profound congenital HI. Two-point and multipoint linkage analyses were performed for the genome scan and fine mapping markers. Haplotypes were constructed to determine the region of homozygosity. At θ = 0, the maximum two-point LOD score of 4.0 was obtained at marker AAC040. A maximum multipoint LOD score of 5.3 was derived at marker D12S320, with the three-unit support interval demarcated by D12S89 and D12S1042. The region of homozygosity is flanked by markers D12S358 and D12S1042, which corresponds to 22.4 cM according to the Rutgers combined linkage-physical map of the human genome and spans 15.0 Mb on the sequence-based physical map. A novel ARNSHI locus DFNB62 was mapped to chromosome 12p13.2-p11.23. DFNB62 represents the second ARNSHI locus to map to chromosome 12.
PMCID: PMC2909107  PMID: 16650082
12p13.2-p11.23; autosomal recessive non-syndromic hearing impairment; DFNB62; Pakistan
12.  Linkage analysis localises a Kartagener syndrome gene to a 3.5 cM region on chromosome 15q24–25 
Primary ciliary dyskinesia (PCD) is a genetic disorder caused by ciliary immotility/dysmotility due to ultrastructural defects of the cilia. Kartagener syndrome (KS), a subtype of PCD, is characterised by situs inversus accompanying the typical PCD symptoms of bronchiectasis and chronic sinusitis. In most cases, PCD is transmitted as an autosomal recessive trait, but its genetic basis is unclear due to extensive genetic heterogeneity.
In a genome‐wide search for PCD loci performed in 52 KS families and in 18 PCD families with no situs inversus present (CDO, ciliary dysfunction‐only), the maximal pairwise LOD score of 3.36 with D15S205 in the KS families indicated linkage of a KS locus to the long arm of chromosome 15. In the follow‐up study, 65 additional microsatellite markers encompassing D15S205 were analysed.
A maximal pairwise LOD score of 4.34 was observed with D15S154, further supporting linkage of the KS, but not the CDO, families to 15q24–25. Analysis of heterogeneity and haplotypes suggested linkage to this region in 60% of KS families.
Reinforced by the results of multipoint linkage, our analyses indicate that a major KS locus is localised within a 3.5 cM region on 15q, between D15S973 and D15S1037.
PMCID: PMC2564509  PMID: 16397065
gene mapping; immotile cilia syndrome; primary ciliary dyskinesia; situs inversus
13.  Identification of a novel locus for triglyceride on chromosome 1p31-32 in families with premature CAD and MI 
Journal of lipid research  2008;49(5):1034-1038.
An increased plasma triglyceride (TG) level is associated with coronary artery disease (CAD) and myocardial infarction (MI) and is a key characteristic of the metabolic syndrome. Here, we used a genome-wide linkage scan to identify a novel genetic locus that influences the plasma TG level. We genotyped 714 persons in 388 multiplex Caucasian families with premature CAD and MI with 408 polymorphic microsatellite markers that cover the entire human genome. The genome-wide scan identified positive linkage for the quantitative TG trait to a novel locus on chromosome 1p31-32 [peak single-point logarithm of odds (LOD) = 3.57, peak multipoint LOD = 3.12]. For single-point linkage analysis, two markers, D1S1728 and D1S551, showed LOD scores of 2.42 and 3.57, respectively. For multipoint linkage analysis, three markers, D1S3736, D1S1728, and D1S551, showed LOD scores of 2.43, 3.03, and 3.12, respectively. No other chromosomal regions showed a LOD score of >2.2.
PMCID: PMC2311437  PMID: 18245017
Supplementary key words: genetics; linkage; coronary artery disease; myocardial infarction; metabolic syndrome
14.  The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). 
Journal of Medical Genetics  1995;32(11):881-884.
Aicardi-Goutières syndrome (Mendelian inheritance in man Catalog No *225750) is an autosomal recessive encephalopathy which causes developmental arrest, intracerebral calcification, and white matter disease in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid interferon-alpha (IFN-alpha). Diagnosis requires the presence of progressive encephalopathy with onset shortly after birth, and characteristic clinical neurological and neuroimaging signs together with chronic CSF lymphocytosis. The syndrome has superficial resemblance to the neurological sequelae of congenital infection, thus a rigorous search for microbiological and serological evidence of embryopathic infections should be carried out in each case.
PMCID: PMC1051740  PMID: 8592332
15.  A linkage study of candidate loci in familial Parkinson's Disease 
BMC Neurology  2003;3:6.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease.
The examined loci were PARK3, Parkin, DRD (dopa-responsive dystonia), FET1 (familial essential tremor), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), Ret, DAT1 (the dopamine transporter), Nurr1 and Synphilin-1. Linkage to the α-synuclein gene and the Frontotemporal dementia with parkinsonism locus on chromosome 17 had previously been excluded in the families included in this study. Using Fastlink, Genehunter and Simwalk both parametric and model-free non-parametric linkage analyses were performed.
In the multipoint parametric linkage analysis lod scores were below -2 for all loci except FET1 and Synphilin-1 under an autosomal dominant model with incomplete penetrance. Using non-parametric linkage analysis there was no evidence for linkage, although linkage could not be excluded. A few families showed positive parametric and non-parametric lod scores indicating possible genetic heterogeneity between families, although these scores did not reach any degree of statistical significance.
We conclude that in these families there was no evidence for linkage to any of the loci tested, although we were unable to exclude linkage with both parametric and non-parametric methods.
PMCID: PMC184377  PMID: 12882651
16.  Two pedigrees segregating Duane’s retraction syndrome as a dominant trait map to the DURS2 genetic locus 
To determine the molecular etiologies of Duane’s retraction syndrome (DRS), we are investigating its genetic bases. We have previously identified the transcription factors SALL4 and HOXA1 as the genes mutated in DRS with radial anomalies, and in DRS with deafness, vascular anomalies, and cognitive deficits, respectively. We know less, however, about the genetic etiology of DRS when it occurs in isolation, and only one genetic locus for isolated DRS, the DURS2 locus on chromosome 2, has been mapped to date. Toward the goal of identifying the DURS2 gene, we have ascertained and studied two pedigrees that segregate DRS as a dominant trait.
We enrolled members of two large dominant DRS pedigrees into our ongoing study of the genetic basis of the congenital cranial dysinnervation disorders, and conducted linkage analysis to determine if their DRS phenotype maps to the DURS2 locus.
By haplotype analysis, the DRS phenotype in each family co-segregates with markers spanning the DURS2 region, and linkage analysis reveals maximum lod scores of >2, establishing that the DRS phenotype in these two pedigrees maps to the DURS2 locus.
These two pedigrees double the published pedigrees known to map to the DURS2 locus, and can thus contribute toward the search for the DURS2 gene. The affected members represent a genetically defined population of DURS2-linked DRS individuals, and hence studies of their clinical and structural features can enhance our understanding of the DURS2 phenotype, as described in the companion paper.
PMCID: PMC2829295  PMID: 17197532
Duane’s syndrome; linkage analysis; DUR2
17.  Quantitative Trait Locus on Chromosome 19 for Circulating Levels of Intercellular Adhesion Molecule-1 in Mexican Americans 
Atherosclerosis  2006;195(2):367-373.
Circulating soluble intercellular adhesion molecule-1 (sICAM-1) is a biochemical marker of inflammation. We performed variance-components-based quantitative genetic analyses in SOLAR of sICAM-1 in 1170 individuals from Mexican American families in the San Antonio Family Heart Study. The trait is heritable (h2 = 0.50±0.06, P<10-6). Multipoint linkage analysis using a ∼10-cM microsatellite map revealed a region on Chromosome 19p near marker D19S586 showing strong evidence of linkage for sICAM-1 (empirically adjusted univariate-equivalent LOD = 4.95), coincident with the structural gene ICAM1. This region has been identified previously as a QTL for inflammatory, autoimmune, and metabolic syndrome traits. There is significant evidence (P=0.0023) of locus heterogeneity for sICAM-1 in this sample: a subset of pedigrees contributes most of the linkage signal for sICAM-1 on Chromosome 19, suggesting a logical focus for future genetic dissection of the trait.
PMCID: PMC2719976  PMID: 17112530
ICAM-1; inflammation; genetic heterogeneity; genome scan; quantitative trait locus; Mexican Americans
18.  A novel susceptibility locus at 2p24 for generalised epilepsy with febrile seizures plus 
Journal of Medical Genetics  2005;42(12):947-952.
Generalised epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous epilepsy syndrome. Using positional cloning strategies, mutations in SCN1B, SCN1A, and GABRG2 have been identified as genetic causes of GEFS+. In the present study, we describe a large four generation family with GEFS+ in which we performed a 10 cM density genome-wide scan. We obtained conclusive evidence for a novel GEFS+ locus on chromosome 2p24 with a maximum two point logarithm of the odds (LOD) score of 4.22 for marker D2S305 at zero recombination. Fine mapping and haplotype segregation analysis in this family delineated a candidate region of 3.24 cM, corresponding to a physical distance of 4.2 Mb. Linkage to 2p24 was confirmed (p = 0.007) in a collection of 50 nuclear and multiplex families with febrile seizures and epilepsy. Transmission disequilibrium testing and association studies provided further evidence (p<0.05) that 2p24 is a susceptibility locus for febrile seizures and epilepsy. Furthermore, we could reduce the candidate region to a 2.14 cM interval, localised between D2S1360 and D2S2342, based upon an ancestral haplotype. Identification of the disease gene at this locus will contribute to a better understanding of the complex genetic aetiology of febrile seizures and epilepsy.
PMCID: PMC1735961  PMID: 15827091
19.  The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity 
Genetic epidemiology  2009;33(7):628-636.
We present the “sumLINK” statistic—the sum of multipoint LOD scores for the subset of pedigrees with nominally significant linkage evidence at a given locus—as an alternative to common methods to identify susceptibility loci in the presence of heterogeneity. We also suggest the “sumLOD” statistic (the sum of positive multipoint LOD scores) as a companion to the sumLINK. SumLINK analysis identifies genetic regions of extreme consistency across pedigrees without regard to negative evidence from unlinked or uninformative pedigrees. Significance is determined by an innovative permutation procedure based on genome shuffling that randomizes linkage information across pedigrees. This procedure for generating the empirical null distribution may be useful for other linkage-based statistics as well. Using 500 genome-wide analyses of simulated null data, we show that the genome shuffling procedure results in the correct type 1 error rates for both the sumLINK and sumLOD. The power of the statistics was tested using 100 sets of simulated genome-wide data from the alternative hypothesis from GAW13. Finally, we illustrate the statistics in an analysis of 190 aggressive prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics, where we identified a new susceptibility locus. We propose that the sumLINK and sumLOD are ideal for collaborative projects and meta-analyses, as they do not require any sharing of identifiable data between contributing institutions. Further, loci identified with the sumLINK have good potential for gene localization via statistical recombinant mapping, as, by definition, several linked pedigrees contribute to each peak.
PMCID: PMC3409837  PMID: 19217022
Methodology; simulation; multipoint linkage; heterogeneity; empirical testing
20.  Significant Evidence of Linkage for a Gene Predisposing to Colorectal Cancer and Multiple Primary Cancers on 22q11 
The genetic basis of colorectal cancer (CRC) is not completely specified. Part of the difficulty in mapping predisposition genes for CRC may be because of phenotypic heterogeneity. Using data from a population genealogy of Utah record linked to a statewide cancer registry, we identified a subset of CRC cases that exhibited familial clustering in excess of that expected for all CRC cases in general, which may represent a genetically homogeneous subset of CRC.
Using a new familial aggregation method referred to as the subset genealogic index of familiality (subsetGIF), combined with detailed information from a statewide tumor registry, we identified a subset of CRC cases that exhibited excess familial clustering above that expected for CRC: CRC cases who had at least one other primary tumor at a different site. A genome-wide linkage analysis was performed on a set of high-risk CRC pedigrees that included multiple CRC cases with additional primaries to identify evidence for predisposition loci.
A total of 13 high-risk CRC pedigrees with multiple CRC cases with other primary cancers were identified. Linkage analysis identified one pedigree with a significant linkage signal at 22q11 (LOD (logarithm (base 10) of odds)=3.39).
A predisposition gene or variant for CRC that also predisposes to other primary cancers likely resides on chromosome 22q11. The ability to use statewide population genealogy and tumor registry data was critical to identify an informative subset of CRC cases that is possibly more genetically homogeneous than CRC in general, and may have improved statistical power for predisposition locus identification in this study.
PMCID: PMC3940837  PMID: 24572700
21.  Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity 
Human genetics  2008;123(3):237.
We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage analysis of the Vietnamese-American family identified the ADDWOC causative locus on chromosome 2q36.1 with a multipoint parametric LOD score of 3.3, while haplotype analysis refined the locus to 1.1 Mb. Sequencing of the five known genes in this locus did not identify any protein-altering mutations. However, a terminal deletion of chromosome 2 in a patient with an isolated case of Dandy-Walker malformation also encompassed the 2q36.1 chromosomal region. The Brazilian pedigree did not show linkage to this 2q36.1 region. Taken together, these results demonstrate a locus for ADDWOC on 2q36.1 and also suggest locus heterogeneity for ADDWOC.
PMCID: PMC2822644  PMID: 18204864
22.  Searching for epistatic interactions in nuclear families using conditional linkage analysis 
BMC Genetics  2005;6(Suppl 1):S148.
Genomic screens generally employ a single-locus strategy for linkage analysis, but this may have low power in the presence of epistasis. Ordered subsets analysis (OSA) is a method for conditional linkage analysis using continuous covariates.
We used OSA to evaluate two-locus interactions in the simulated Genetic Analysis Workshop 14 dataset. We used all nuclear families ascertained by Aipotu, Karangar, and Danacaa. Using the single-nucleotide polymorphism map, multipoint affected-sibling-pair (ASP) linkage analysis was performed on all 100 replicates for each chromosome using SIBLINK. OSA was used to examine linkage on each chromosome using LOD scores at each 3-cM location on every other chromosome as covariates. Two methods were used to identify positive results: one searching across the entire covariate chromosome, the other conditioning on location of known disease loci.
Single-locus linkage analysis revealed very high LOD scores for disease loci D1 through D4, with mean LOD scores over 100 replicates ranging from 4.0 to 7.8. Although OSA did not obscure this linkage evidence, it did not detect the simulated interactions between any of the locus pairs. We found inflated type I error rates using the first OSA method, highlighting the need to correct for multiple comparisons. Therefore, using "null chromosome pairs" without simulated disease loci, we calculated a corrected alpha-level.
We were unable to detect two-locus interactions using OSA. This may have been due to lack of incorporation of phenotypic subgroups, or because linkage evidence as summarized by LOD scores performs poorly as an OSA covariate. We found inflated type I error rates, but were able to calculate a corrected alpha-level for future analyses employing this strategy to search for two-locus interactions.
PMCID: PMC1866787  PMID: 16451608
23.  Localization of a novel autosomal recessive non-syndromic hearing impairment locus DFNB55 to chromosome 4q12-q13.2 
Clinical genetics  2005;68(3):262-267.
Hereditary hearing impairment (HI) is the most genetically heterogeneous trait known in humans. So far, 54 autosomal recessive non-syndromic hearing impairment (ARNSHI) loci have been mapped, and 21 ARNSHI genes have been identified. Here is reported the mapping of a novel ARNSHI locus, DFNB55, to chromosome 4q12-q13.2 in a consanguineous Pakistani family. A maximum multipoint LOD score of 3.5 was obtained at marker D4S2638. The region of homozygosity and the 3-unit support interval are flanked by markers D4S2978 and D4S2367. The region spans 8.2 cM on the Rutgers combined linkage-physical map and contains 11.5 Mb. DFNB55 represents the third ARNSHI locus mapped to chromosome 4.
PMCID: PMC2910366  PMID: 16098016
4q12-q13.2; autosomal recessive non-syndromic hearing impairment; DFNB55; Pakistan
24.  Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study 
BMC Genetics  2003;4(Suppl 1):S52.
Epidemiological studies have indicated that obesity and low high-density lipoprotein (HDL) levels are strong cardiovascular risk factors, and that these traits are inversely correlated. Despite the belief that these traits are correlated in part due to pleiotropy, knowledge on specific genes commonly affecting obesity and dyslipidemia is very limited. To address this issue, we first conducted univariate multipoint linkage analysis for body mass index (BMI) and HDL-C to identify loci influencing variation in these phenotypes using Framingham Heart Study data relating to 1702 subjects distributed across 330 pedigrees. Subsequently, we performed bivariate multipoint linkage analysis to detect common loci influencing covariation between these two traits.
We scanned the genome and identified a major locus near marker D6S1009 influencing variation in BMI (LOD = 3.9) using the program SOLAR. We also identified a major locus for HDL-C near marker D2S1334 on chromosome 2 (LOD = 3.5) and another region near marker D6S1009 on chromosome 6 with suggestive evidence for linkage (LOD = 2.7). Since these two phenotypes have been independently mapped to the same region on chromosome 6q, we used the bivariate multipoint linkage approach using SOLAR. The bivariate linkage analysis of BMI and HDL-C implicated the genetic region near marker D6S1009 as harboring a major gene commonly influencing these phenotypes (bivariate LOD = 6.2; LODeq = 5.5) and appears to improve power to map the correlated traits to a region, precisely.
We found substantial evidence for a quantitative trait locus with pleiotropic effects, which appears to influence both BMI and HDL-C phenotypes in the Framingham data.
PMCID: PMC1866489  PMID: 14975120
25.  Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q 
BMC Cancer  2008;8:87.
Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer.
Statistical analysis was performed using multipoint parametric and nonparametric linkage.
Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1).
The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.
PMCID: PMC2324103  PMID: 18380902

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