Suggestive Evidence For Linkage Research Articles

A 127\u2009kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract

Inherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye’s crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24–25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24–25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 (PGRMC1) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein–protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1, which we report as a novel cataract gene.

'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41-200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson's disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.

Whole Genome Linkage Scan Identifies a Novel Locus on 3q28 for TG/HDL-C Ratio Change Over Time

TG/HDL-C ratio (THR) represents a single inherited surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify genetic loci for THR change over time (ΔTHR), we conducted a whole genome linkage scan among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=3091), a study with familial clustering of exceptional longevity in the US and Denmark. Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, PCs, familial membership, and then log-transformed to approximate normality. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%), and evidence for significant linkage (LOD>3) was identified on 3q28 (LOD=4.1). This locus harbors ADIPOQ among several other promising candidate genes. Interestingly, several studies previously reported suggestive evidence of linkage at this locus for relevant traits including adiponectin, dementia, AD and SBP. This linkage signal was not explained by significant GWAS SNPs for LPL or those under the peak (LOD attenuated to 3.7). In conclusion, we found a novel genetic locus on 3q28 for ΔTHR in subjects without diabetes selected for exceptional survival and healthy aging. Further query of sequence elements including rare functional and regulatory variants at this locus is underway which may reveal novel insights on insulin resistance mechanisms for aging.

Pedigree-Based Gene Mapping Supports Previous Loci and Reveals Novel Suggestive Loci in Specific Language Impairment.

PurposeSpecific language impairment (SLI) is characterized by a delay in language acquisition despite a lack of other developmental delays or hearing loss. Genetics of SLI is poorly understood. The purpose of this study is to identify SLI genetic loci through family-based linkage mapping.MethodWe performed genome-wide parametric linkage analysis in six families segregating with SLI. An age-appropriate standardized omnibus language measure was used to categorically define the SLI phenotype.ResultsA suggestive linkage region replicated a previous region of interest with the highest logarithm of odds (LOD) score of 2.40 at 14q11.2-q13.3 in Family 489. A paternal parent-of-origin effect associated with SLI and language phenotypes on a nonsynonymous single nucleotide polymorphism (SNP) in NOP9 (14q12) was reported previously. Linkage analysis identified a new SLI locus at 15q24.3-25.3 with the highest parametric LOD score of 3.06 in Family 315 under a recessive mode of inheritance. Suggestive evidence of linkage was also revealed at 4q31.23-q35.2 in Family 300, with the highest LOD score of 2.41. Genetic linkage was not identified in the other three families included in parametric linkage analysis.ConclusionsThese results are the first to report genome-wide suggestive linkage with a total language standard score on an age-appropriate omnibus language measure across a wide age range. Our findings confirm previous reports of a language-associated locus on chromosome 14q, report new SLI loci, and validate the pedigree-based parametric linkage analysis approach to mapping genes for SLI.Supplemental Material https://doi.org/10.23641/asha.13203218

Genome-wide analysis of high-risk primary brain cancer pedigrees identifies PDXDC1 as a candidate brain cancer predisposition gene.

There is evidence for an inherited contribution to primary brain cancer. Linkage analysis of high-risk brain cancer pedigrees has identified candidate regions of interest in which brain cancer predisposition genes are likely to reside. Genome-wide linkage analysis was performed in a unique set of 11 informative, extended, high-risk primary brain cancer pedigrees identified in a population genealogy database, which include from 2 to 6 sampled, related primary brain cancer cases. Access to formalin-fixed paraffin embedded tissue samples archived in a biorepository allowed analysis of extended pedigrees. Individual high-risk pedigrees were singly informative for linkage at multiple regions. Suggestive evidence for linkage was observed on chromosomes 2, 3, 14, and 16. The chromosome 16 region in particular contains a promising candidate gene, pyridoxal-dependent decarboxylase domain-containing 1 (PDXDC1), with prior evidence for involvement with glioblastoma from other previously reported experimental settings, and contains the lead single nucleotide polymorphism (rs3198697) from the linkage analysis of the chromosome 16 region. Pedigrees with a statistical excess of primary brain cancers have been identified in a unique genealogy resource representing the homogeneous Utah population. Genome-wide linkage analysis of these pedigrees has identified a potential candidate predisposition gene, as well as multiple candidate regions that could harbor predisposition loci, and for which further analysis is suggested.

Evidence for gene-smoking interactions for hearing loss and deafness in Japanese American families

BackgroundThis study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with smoking using logistic regression models. ResultsAfter adjusting for age, sex, diabetes status and smoking duration, for each pack of cigarettes smoked per day, risk of HLD increased 4.58 times (odds ratio (OR) = 4.58; 95% Confidence Interval (CI): (1.40,15.03)), and ever smokers were over 5 times more likely than nonsmokers to report HLD (OR = 5.22; 95% CI: (1.24, 22.03)). Suggestive evidence for linkage for HLD was observed in multiple genomic regions (Chromosomes 5p15, 8p23 and 17q21), and additional suggestive regions were identified when considering interactions with smoking status (Chromosomes 7p21, 11q23, 12q32, 15q26, and 20q13) and packs-per-day (Chromosome 8q21). ConclusionsTo our knowledge this was the first report of possible gene-by-smoking interactions in HLD using family data. Additional work, including independent replication, is needed to understand the basis of these findings. HLD are important public health issues and understanding the contributions of genetic and environmental factors may inform public health messages and policies.

CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes.

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 × 10−4 for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the β2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.

Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33.

Myopia is one of the most common ocular disorders in the world, yet the genetic etiology of the disease remains poorly understood. Specialized founder populations, such as the Pennsylvania Amish, provide the opportunity to utilize exclusive genomic architecture, like unique haplotypes, to better understand the genetic causes of myopia. We perform genetic linkage analysis on Pennsylvania Amish families that have a strong familial history of myopia to map any potential causal variants and genes for the disease. 293 individuals from 25 extended families were genotyped on the Illumina ExomePlus array and merged with previous microsatellite data. We coded myopia affection as a binary phenotype; myopia was defined as having a mean spherical equivalent (MSE) of less than or equal to - 1 D (diopters). Two-point and multipoint parametric linkage analyses were performed under an autosomal dominant model. When allowing for locus heterogeneity, we identified two novel genome-wide significantly linked variants at 12q15 (heterogeneity LOD, HLOD = 3.77) in PTPRB and at 8q21.3 (HLOD = 3.35) in CNGB3. We identified further three genome-wide significant variants within a single family. These three variants were located in exons of SLC6A18 at 5p15.33 (LODs ranged from 3.51 to 3.37). Multipoint analysis confirmed the significant signal at 5p15.33 with six genome-wide significant variants (LODs ranged from 3.6 to 3.3). Further suggestive evidence of linkage was observed in several other regions of the genome. All three novel linked regions contain strong candidate genes, especially CNGB3 on 8q21.3, which has been shown to affect photoreceptors and cause complete color blindness. Whole genome sequencing on these regions is planned to conclusively elucidate the causal variants.

Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family

Background: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. Objective: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations. Methods: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls. Results: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8–2.4), p = 0.31). Conclusion: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk.

Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q.

The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.

Significant Linkage Evidence for Interstitial Cystitis/Painful Bladder Syndrome on Chromosome 3.

Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etiology. We hypothesized that related interstitial cystitis/painful bladder syndrome cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis. We identified interstitial cystitis/painful bladder syndrome cases using diagnostic codes linked to the Utah Population Database genealogy resource and to electronic medical records. For this analysis we used 13 high risk pedigrees, defined as having a statistical excess number of interstitial cystitis/painful bladder syndrome cases among descendants compared to matched hospital population rates. Case status was confirmed in medical records using natural language processing. DNA was obtained from stored, nonneoplastic, formalin fixed, paraffin embedded tissue blocks. Each pedigree had at least 2 cases with DNA available. Parametric linkage analysis was performed. Pedigrees ranged in size from 2 to 12 genotyped cases for a total of 48 cases. Significant genome wide linkage evidence was found under a dominant model on chromosome 3p13-p12.3 (maximum heterogeneity θ logarithm of odds 3.56). Two pedigrees showed at least nominal linkage evidence in this region (logarithm of odds greater than 0.59). The most informative pedigree included 12 interstitial cystitis/painful bladder syndrome cases (pedigree θ logarithm of odds 2.1). Other regions with suggestive linkage evidence included 1p21-q25, 3p21.1-p14.3, 4q12-q13, 9p24-p22 and 14q24-q31, all under a dominant model. While the etiology of interstitial cystitis/painful bladder syndrome is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 and possibly on chromosomes 1, 4, 9 and 14 contribute to an interstitial cystitis/painful bladder syndrome predisposition. Sequence analysis of affected cases in identified pedigrees may provide insight into genes contributing to interstitial cystitis/painful bladder syndrome.

Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p.

PurposeMyopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia.MethodsIndividuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed.ResultsSingle variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13.ConclusionsWe identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region.

A genome-wide quantitative trait locus (QTL) linkage scan of NEO personality factors in Latino families segregating bipolar disorder.

Personality traits have been suggested as potential endophenotypes for Bipolar Disorder (BP), as they can be quantitatively measured and show correlations with BP. The present study utilized data from 2,745 individuals from 686 extended pedigrees originally ascertained for having multiplex cases of BP (963 cases of BPI or schizoaffective BP). Subjects were assessed with the NEO Personality Inventory, Revised (NEO PI-R) and genotyped using the Illumina HumanLinkage-24 Bead Chip, with an average genetic coverage of 0.67 cM. Two point linkage scores were calculated for each trait as a quantitative variable using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Suggestive evidence for linkage was found for neuroticism at 1q32.1 (LOD = 2.52), 6q23.3 (2.32), 16p12 (2.79), extraversion at 4p15.3 (2.33), agreeableness at 4q31.1 (2.37), 5q34 (2.80), 7q31.1 (2.56), 16q22 (2.52), and conscientiousness at 4q31.1 (2.50). Each of the above traits have been shown to be correlated with the broad BP phenotype in this same sample. In addition, for the trait of openness, we found significant evidence of linkage to chromosome 3p24.3 (rs336610, LOD = 4.75) and suggestive evidence at 1q43 (2.74), 5q35.1 (3.03), 11q14.3 (2.61), 11q21 (2.30), and 19q13.1 (2.52). These findings support previous linkage findings of the openness trait to chromosome 19q13 and the agreeableness trait to 4q31 and identify a number of new loci for personality endophenotypes related to bipolar disorder.

PD01-05 SIGNIFICANT LINKAGE EVIDENCE FOR INTERSTITIAL CYSTITIS/PAINFUL BLADDER SYNDROME ON CHROMOSOME 3

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis I1 Apr 2017PD01-05 SIGNIFICANT LINKAGE EVIDENCE FOR INTERSTITIAL CYSTITIS/PAINFUL BLADDER SYNDROME ON CHROMOSOME 3 Kristina Allen-Brady, Kerry Rowe, Melissa Cessna, and Peggy Norton Kristina Allen-BradyKristina Allen-Brady More articles by this author , Kerry RoweKerry Rowe More articles by this author , Melissa CessnaMelissa Cessna More articles by this author , and Peggy NortonPeggy Norton More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.185AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic pain condition with unknown etiology. Family history is one of the strongest known risk factors, suggesting a genetic contribution. We hypothesized that related IC/PBS cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis for IC/PBS. METHODS Using the Utah Population Database (a population-based genealogy resource linked to medical records at the largest Utah healthcare provider), 13 high-risk pedigrees (defined as having a statistical excess (p<0.05) of IC/PBS cases among relatives who were hospital patients compared to expected number of cases using age- and sex-matched hospital rates for IC/PBS) were used for this analysis. Each pedigree had at least two sampled cases; case status was confirmed in the medical record using natural language processing. DNA was obtained from stored, non-cancerous, formalin-fixed, paraffin-embedded (FFPE) tissue blocks (e.g., appendix). Pedigrees ranged in size from 2 to 12 genotyped cases (n=48). Genotype data were obtained from Illumina OmniExpress BeadChip array (~710, 0000 SNPs); all SNPs passed quality control filters prior to linkage analysis. We eliminated highly correlated SNP markers (i.e., high linkage disequilibrium). Parametric linkage analysis using general dominant and recessive models was performed using the Markov Chain, Monte Carlo linkage analysis method, MCLINK. Results are reported as heterogeneity logarithm of odds scores (HLODs), defined as suggestive (HLOD ≥ 1.86) and significant (HLOD ≥ 3.3) linkage evidence. We also reported the number of individual pedigrees considered ″linked″ to a significant genomic peak (i.e., pedigree LOD score ≥ 0.588). RESULTS Significant genome-wide linkage evidence was found on chromosome 3p21-3q13 with a maximum HLOD score of 3.56 under a dominant model. There were 4 pedigrees (30.8%) that had at least nominal linkage evidence (LOD ≥ 0.588) in this region. The most informative pedigree for linkage included 12 IC/PBS cases and had an individual LOD score of 2.1 in this region. Other regions with suggestive evidence for linkage included 1p21-1q25, 4q12-13, 9p24-22, and 14q24, all under a dominant model. CONCLUSIONS While the etiology of IC/PBS is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 likely contributes to IC/PBS predisposition. Further study of the pedigrees underlying this significant linkage evidence and sequence analysis of the affected cases may provide insight into genes contributing to IC/PBS. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e47-e48 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kristina Allen-Brady More articles by this author Kerry Rowe More articles by this author Melissa Cessna More articles by this author Peggy Norton More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

GREB1 genetic variants are associated with bone mineral density in Caucasians

Gaining an understanding of factors contributing to bone quality is key to the development of effective preventative treatments for osteoporosis and reduction in osteoporotic fractures. Oestrogen is a strong regulator of bone remodelling which maintains skeletal structural integrity. The growth regulation by oestrogen in breast cancer 1 (GREB1) gene, with an as yet undefined function, is an early response gene in the oestrogen-regulated pathway. Suggestive evidence of linkage with bone mineral density (BMD) variation has been reported with D2S168, located telomeric of GREB1. The aim of this study was to determine if genetic variation within GREB1 was associated with BMD variation at two sites with high fracture rates-the lumbar spine (LS) and the femoral neck (FN). Informative GREB1 single-nucleotide polymorphisms (SNPs) (n=12) were selected for genotyping and tested for association in a family-based dataset (n=508 individuals from 229 families). Significantly associated SNPs were tested further in a postmenopausal dataset from the same geographic region (n=477 individuals). One intronic SNP, rs5020877, was significantly associated with LS and FN BMD in the family-based dataset (P≤0.005). The association was not observed in the postmenopausal dataset (P>0.017); however, rs10929757 was significantly associated with FN BMD (P=0.006). Markers, rs5020877 and rs10929757, were constituent SNPs in one GREB1 linkage disequilibrium block, although not historically correlated (r 2=0.07). Our findings suggest that GREB1 is a novel gene target for osteoporosis genetics and needs to be investigated further.

A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate.

Acrophobia, an abnormal fear of heights, is a specific phobia characterized as apprehension cued by the occurrence or anticipation of elevated spaces. It is considered a complex trait with onset influenced by both genetic and environmental factors. Identification of genetic risk variants would provide novel insight into the genetic basis of the fear of heights phenotype and contribute to the molecular-level understanding of its aetiology. Genetic isolates may facilitate identification of susceptibility alleles due to reduced genetic heterogeneity. We took advantage of an internal genetic isolate in Finland in which a distinct acrophobia phenotype appears to be segregating in pedigrees originally ascertained for schizophrenia. We conducted parametric, nonparametric, joint linkage and linkage disequilibrium analyses using a microsatellite marker panel, genotyped in families to search for chromosomal regions correlated with acrophobia. Our results implicated a few regions with suggestive evidence for linkage on chromosomes 4q28 (LOD = 2.17), 8q24 (LOD = 2.09) and 13q21-q22 (LOD = 2.22). We observed no risk haplotypes shared between different families. These results suggest that genetic predisposition to acrophobia in this genetic isolate is unlikely to be mediated by a small number of shared high-risk alleles, but rather has a complex genetic architecture.

Linkage analysis in a Dutch population isolate shows no major gene for left-handedness or atypical language lateralization.

Cerebral dominance of language function and hand preference are suggested to be heritable traits with possible shared genetic background. However, joined genetic studies of these traits have never been conducted. We performed a genetic linkage study in 37 multigenerational human pedigrees of both sexes (consisting of 355 subjects) enriched with left-handedness in which we also measured language lateralization. Hand preference was measured with the Edinburgh Handedness Inventory, and language lateralization was measured with functional transcranial Doppler during language production. The estimated heritability of left-handedness and language lateralization in these pedigrees is 0.24 and 0.31, respectively. A parametric major gene model was tested for left-handedness. Nonparametric analyses were performed for left-handedness, atypical lateralization, and degree of language lateralization. We did not observe genome-wide evidence for linkage in the parametric or nonparametric analyses for any of the phenotypes tested. However, multiple regions showed suggestive evidence of linkage. The parametric model showed suggestive linkage for left-handedness in the 22q13 region [heterogeneity logarithm of odds (HLOD) = 2.18]. Nonparametric multipoint analysis of left-handedness showed suggestive linkage in the same region [logarithm of odds (LOD) = 2.80]. Atypical language lateralization showed suggestive linkage in the 7q34 region (LODMax = 2.35). For strength of language lateralization, we observed suggestive linkage in the 6p22 (LODMax = 2.54), 7q32 (LODMax = 1.93), and 9q33 (LODMax = 2.10) regions. We did not observe any overlap of suggestive genetic signal between handedness and the extent of language lateralization. The absence of significant linkage argues against the presence of a major gene coding for both traits; rather, our results are suggestive of these traits being two independent polygenic complex traits.

Clinical and genetic analysis of a family with two rare reflex epilepsies

PurposeTo determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. MethodPhenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. ResultsThe proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR.Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years.Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. ConclusionThis family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.

ACN9 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families.

A previous genome-wide linkage study of alcohol dependence (AD) in the Pittsburgh-based multiplex family study found suggestive evidence for linkage on Chromosome 7q, a region in which the ACN9 gene is located. Using the same two generation Pittsburgh family data in which linkage was found, data for a third generation was added. The expanded sample included 133 pedigrees with 995 individuals. Finer mapping was undertaken using six SNPs extending from rs1917939 to rs13475 with minor allele frequency (MAF) ≥0.15 and pair-wise linkage disequilibrium (LD) of r(2) <0.8 using the HapMap CEU population. Binary affection status, visual, and auditory P300 data were tested for family-based association. Family-based analyses found all six SNPs associated with affected status. Three SNPs are located upstream of the gene, two SNPs are within intron 1 and one is in Exon 4. FBAT P-values for the six SNPs ranged between 0.05 and 0.0005. Haplotype analysis revealed one four-SNP block formed by rs10499934, rs7794886, rs12056091, and rs13475 with an overall significant association at P = 0.0008. Analysis of visual P300 amplitude data, a known endophenotype of alcohol dependence risk, revealed a significant association for SNPs within intron 1 and exon 4 under a dominant model of transmission. Family-based association analysis shows the ACN9 gene significantly associated with alcohol dependence and P300 amplitude variation. The potential importance of the ACN9 gene for AD risk may be related to its role in gluconeogenesis which may be involved in the regulation of alcohol metabolism.

Identification of susceptibility loci in hereditary prostate cancer families using copy number variation and linkage analysis.

232 Background: Family history is one of the most significant predictor of prostate cancer risk. With approximately 10% of prostate cancer cases attributable to inheritable genetic factors. However, disease gene identification for prostate cancer has been extremely challenging due to both disease and genetic heterogeneity. Therefore, the goal of this study was to employ an array of genetic tools in order to characterize germline variants in seven high-risk families with prostate cancer. Methods: To overcome the effects of ethnic disparity, genetic heterogeneity, incomplete penetrance, and missing heritability, we utilized a comprehensive approach that combines both array comparative genomic hybridization (aCGH) analysis and linkage analysis to identify genetic components of prostate cancer. Seven prostate cancer cases were studied using aCGH to search for germ-line copy number variants (CNVs) associated with hereditary prostate cancer. The study subjects were from 7 large, high-risk, clinically homogenous families with European ancestry from Southern Louisiana. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. Results: Three novel regions of CNVs were identified: 16q23, 11q22, and 2q22 in all 7 prostate cancer cases from high-risk families. Both model-based and model-free linkage analyses were performed on 4 of the most informative families (≥5 prostate cancer patients per family). Suggestive evidence of linkage was obtained at 2q14 (HLOD score of 1.94). Using aCGH, a 68 kb duplication was observed in this region in all 7 hereditary prostate cancer cases. Conclusions: These genetic findings, which were identified in multiple large, well-characterized families, provide new insight into hereditary prostate cancer. A combination of future fine mapping of the 2q14 region in a larger cohort of patients, confirmation of these novel CNVs in additional subjects, and use of next-generation sequencing approaches to search for potential disease-associated genetic alterations are needed to provide further characterization of these prostate cancer associated susceptibility loci.