Significant Evidence For Linkage Research Articles

Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology.

SummaryBackgroundEssential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic tremor of the arms and, in some patients, tremor involving other body regions (e.g., head, voice). Genetic studies suggest that ET is genetically heterogeneous.MethodsWe analyzed whole genome sequence data (WGS) generated on 104 multi-generational white families with European ancestry affected by ET. Genome-wide parametric linkage and association scans were analyzed using adjusted logistic regression models through the application of the Pseudomarker software. To investigate the additional contribution of rare variants in familial ET, we also performed an aggregate variant non-parametric linkage (NPL) analysis using the collapsed haplotype method implemented in CHP-NPL software.FindingsParametric linkage analysis of common variants identified several loci with significant evidence of linkage (HLOD ≥3.6). Among the gene regions within the strongest ET linkage peaks were BTC (4q13.3, HLOD=4.53), N6AMT1 (21q21.3, HLOD=4.31), PCDH9 (13q21.32, HLOD=4.21), EYA1 (8q13.3, HLOD=4.04), RBFOX1 (16p13.3, HLOD=4.02), MAPT (17q21.31, HLOD=3.99) and SCARB2 (4q21.1, HLOD=3.65). CHP-NPL analysis identified fifteen additional genes with evidence of significant linkage (LOD ≥3.8). These genes include TUBB2A, VPS33B, STEAP1B, SPINK5, ZRANB1, TBC1D3C, PDPR, NPY4R, ETS2, ZNF736, SPATA21, ARL17A, PZP, BLK and CCDC94. In one ET family contributing to the linkage peak on chromosome 16p13.3, we identified a likely pathogenic heterozygous canonical splice acceptor variant in exon 2 of RBFOX1 (ENST00000547372; c.4-2A>G), that co-segregated with the ET phenotype in the family.InterpretationLinkage and association analyses of WGS identified several novel ET candidate genes, which are implicated in four major pathways that include 1) the epidermal growth factor receptor-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-AKT serine/threonine kinase 1 (EGFR-PI3K-AKT) and Mitogen-activated protein Kinase 1 (ERK) pathways, 2) Reactive oxygen species (ROS) and DNA repair, 3) gamma-aminobutyric acid-ergic (GABAergic) system and 4) RNA binding and regulation of RNA processes. Our study provides evidence for a possible overlap in the genetic architecture of ET, neurological disease, cancer and aging. The genes and pathways identified can be prioritized in future genetic and functional studies.FundingNational Institutes of Health, NINDS, NS073872 (USA) and NIA AG058131(USA).

Identification of a Novel Locus for Gait Speed Decline With Aging: The Long Life Family Study.

Gait speed is a powerful indicator of health with aging. Potential genetic contributions to gait speed and its decline with aging are not well defined. We determined the heritability of and potential genetic regions underlying change in gait speed using longitudinal data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30-110 years; 45% men). Gait speed was measured over 4 m at baseline and follow-up (7 ± 1 years). Quantitative trait linkage analyses were completed using pedigree-based maximum likelihood methods with logarithm of the odds (LOD) scores greater than 3.0, indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height, and field center. At baseline, 26.9% of individuals had "slow" gait speed less than 1.0 m/s (mean: 1.1 ± 0.2 m/s) and gait speed declined at a rate of -0.02 ± 0.03 m/s per year (p < .0001). Baseline and change in gait speed were significantly heritable (h2 = 0.24-0.32, p < .05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a significant locus for change in gait speed on chromosome 16p (LOD = 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Association analyses on chromosome 16 showed that the strongest variant resides within the ADCY9 gene. Further analysis of the chromosome 16 region, and ADCY9 gene, may yield new insight on the biology of mobility decline with aging.

Investigating the dynamic linkages among carbon dioxide emissions, economic growth, and renewable and non-renewable energy consumption: evidence from developing countries.

This research paper examines the causal relationships among carbon dioxide emissions, economic growth, and renewable and non-renewable energy consumption, for a panel of 68 developing countries over the period 1990 - 2014. We use the multivariate panel cointegration framework and apply a battery of conventional (Pedroni 1999, 2004; and Kao 1999) as well as newly developed methodologies accounting for heterogeneity and cross-sectional correlation (Westerlund's ECM panel cointegration (2007) and panel bootstrap cointegration (2007) tests). The pooled mean group (PMG), mean group (MG), and dynamic fixed effects (DFE) methodologies were further applied to trace out the short-run dynamics. The results support evidence of significant dynamic linkages among the involved variables and reveal possible differences in the magnitude of the impacts from renewable and non-renewable energy consumption on environmental quality. The issue of distinguishing by source and determining the magnitude of the detected effects could provide valuable information for a sustainable economic and environmental development, substantially helping policy makers to designate more efficient policy measures.

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.

Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4-19years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry. Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P<2.8×10-9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score>3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P=4.6×10-8), and between pelvis BMD and rs7000615 at PTK2B (P=7.4×10-8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P<9×10-7). We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.

GENOME-WIDE LINKAGE ANALYSIS IDENTIFIES A NOVEL LOCUS FOR LONGITUDINAL GAIT SPEED CHANGE WITH AGING

Gait speed is an indicator of health and function with aging. The potential genetic contributions to gait speed and its decline with aging are not well characterized. We sought to better quantify the genetic contributions to and identify potential genes and genetic variants underlying change in gait speed among older adults. To accomplish these aims, we used data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30–110 years; 45% men). Gait-speed was measured over 4 meters at baseline and after an average of 7±1.1 years. Quantitative trait linkage analyses were completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores > 3.3 indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height and field center. At baseline, 26.9% of individuals had “low” gait-speed <1.0 m/s (mean: 1.1±0.2 m/s) and gait speed declined at a rate of -0.02±0.03 m/s per year (p<0.0001). Baseline and change in gait-speed were significantly heritable (h2 = 0.24-0.32, p<0.05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a potentially novel locus for change in gait speed on chromosome 16p (LOD 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Sequence analysis of the chromosome 16 region may yield new insight on the biology of age-related mobility decline.

MiR-183-5p Inhibits Occurrence and Progression of Acute Myeloid Leukemia via Targeting Erbin.

Erbin has been shown to have significant effects on the development of solid tumors. However, little is known about its function and regulatory mechanism in hematological malignancies. The biological function of Erbin on cell proliferation was measured in vitro and in vivo. The predicted target of Erbin was validated by dual-luciferase reporter assay and rescue experiment. We found that overexpression of Erbin could inhibit the cell proliferation and promote the cell differentiation of acute myeloid leukemia (AML) cells, whereas depletion of Erbin could enhance the cell proliferation and block the cell differentiation in AML cells in vitro and in vivo. Besides, miR-183-5p was identified as the upstream regulator that negatively regulated the Erbin expression. The results were confirmed by dual-luciferase reporter and RNA pull-down assay. Furthermore, we found that miR-183-5p negatively regulated Erbin, resulting in enhanced cell proliferation of AML cells via activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways. The activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways was mediated by Erbin interacting with Grb2. These results were also validated by rescue experiments in vitro and in vivo. All above-mentioned findings indicated that the miR-183-5p/Erbin signaling pathway might represent a novel prognostic biomarker or therapeutic target for treatment of AML.

Large-Scale Linkage Analysis of Multiple Myeloma (MM) and Monoclonal Gammopathy of Undetermined Significance (MGUS) Families

Introduction Multiple myeloma (MM) is a result of a malignant transformation of plasma cells that is preceded by the presence of an asymptomatic clonal plasma cell expansion, a condition referred to as monoclonal gammopathy of undetermined significance (MGUS). We and others have shown familial aggregation of MM and MGUS. Evidence from epidemiologic, family and genome-wide association studies (GWAS) suggests a genetic component underlying MM etiology. GWAS have successfully established 17 common genetic risk loci for MM to date and recently, rare inherited susceptibility variants in the LSD1 / KDM1A and USP45 genes were identified in familial MM / MGUS kindreds. Family-based approaches may be used to elucidate genetic variation contributing to familial MM. Genetic linkage analysis has historically been used to detect the chromosomal location of disease genes. The objective of this study was to conduct a linkage analysis of MM / MGUS families to identify genomic regions for MM / MGUS. Methods Linkage analysis was performed on whole exome sequencing (WES) data generated from germline DNA extracted from peripheral blood from MM / MGUS families ascertained at four sites, of which 79 were selected with 2 or more affected members with any combination of MM or MGUS. Whole exome capture was performed using Agilent SureSelect 38 Mb paired end sequencing and ran on Illumina HiSeq 2000s/2500s; standard analyses for alignment (GRCh37) and quality control were conducted. The Genome Analysis Toolkit9s (GATK) HaplotypeCaller in per-sample mode was used to jointly call all the samples together. Quality control included removing variants that had Results Among the 79 families, 28 consisted of two or more MM, 41 had two or more MM and MGUS cases and 10 had two or more MGUS. Analyses of the 79 MM / MGUS families identified chromosome 6 at 123420001-149070000 BP region, with evidence for linkage by the non-parametric model (LOD score=3.3) and supportive evidence for linkage by the dominant parametric model (LOD=2.5) (Figure). The chromosome 6 region, which is outside the HLA-region, contains a total of 72 genes. Using gene-level association tests, we identified four genes within the region (MOXD1, TRDN, ADAT2, LTV1) that were associated within MM / MGUS in the family cases (p Discussion We found evidence for a locus on chromosome 6 linked to MM / MGUS. Four genes in this region may be associated with MM / MGUS in these families. Follow-up of these genes/variants in high-risk individuals (early-onset / age Disclosures Dumontet:Roche: Research Funding; Merck: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria. Kumar:AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees; Merck: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Whole-Genome Linkage Scan Combined With Exome Sequencing Identifies Novel Candidate Genes for Carotid Intima-Media Thickness.

Carotid intima-media thickness (cIMT) is an established heritable marker for subclinical atherosclerosis. In this study, we aim to identify rare variants with large effects driving differences in cIMT by performing genome-wide linkage analysis of individuals in the extremes of cIMT trait distribution (>90th percentile) in a large family-based study from a genetically isolated population in the Netherlands. Linked regions were subsequently explored by fine-mapping using exome sequencing. We observed significant evidence of linkage on chromosomes 2p16.3 [rs1017418, heterogeneity LOD (HLOD) = 3.35], 19q13.43 (rs3499, HLOD = 9.09), 20p13 (rs1434789, HLOD = 4.10), and 21q22.12 (rs2834949, HLOD = 3.59). Fine-mapping using exome sequencing data identified a non-coding variant (rs62165235) in PNPT1 gene under the linkage peak at chromosome 2 that is likely to have a regulatory function. The variant was associated with quantitative cIMT in the family-based study population (effect = 0.27, p-value = 0.013). Furthermore, we identified several genes under the linkage peak at chromosome 21 highly expressed in tissues relevant for atherosclerosis. To conclude, our linkage analysis identified four genomic regions significantly linked to cIMT. Further analyses are needed to demonstrate involvement of identified candidate genes in development of atherosclerosis.

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.

A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.

Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14–15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4–11q14.1 (LOD = 3.71) and 5q14.3–5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-genome sequencing should further confirm the associations at chromosome 11 and investigate the chromosome 15 and 5 linked regions.

Abstract P132: Genome-wide Linkage Analysis of Carotid Artery Traits in Exceptionally Long-Lived Families

The extent to which genetics plays a role in vascular health in exceptional aging has not been established. We performed genetic heritability and genome-wide linkage analysis of carotid artery ultrasound derived traits in 1931 individuals (3913 relative pairs) from the Long Life Family Study (LLFS). The LLFS is a longitudinal family-based cohort study that recruited long-lived individuals and at least 1 of their long-lived siblings, as well as, all offspring and offspring spouses. Participants had a home visit that included B-mode carotid artery ultrasound to assess inter-adventitial diameter (IAD), common carotid artery far wall (FW) intima-media thickness (IMT), lumen diameter (LD), and carotid plaque prevalence and burden. We conducted residual heritability analyses for each of these traits, adjusted for age, age 2 , sex, and field center (4 sites) using pedigree-based maximum-likelihood methods in SOLAR. Linkage markers were haplotypes generated from genotypes typed on the Human Omni Chip 2.5 v1 (Illumina, CA) and multipoint identity-by-descent estimates were calculated by Loki. Multipoint genome-wide (chr 1-22) linkage analysis was conducted in SOLAR. Chromosomal regions were considered significant if the logarithm of the odds (LOD) score was ≥3.0 (suggestive: LOD ≥2.0). Proband and offspring generations, respectively, were 59% and 55% female and had mean ages of 97.3 and 73.5 years. Carotid traits were significantly heritable, ranging from 0.37 for mean FW IMT to 0.67 for mean IAD. We found significant evidence of linkage on chromosome 3 at 125 cM (max LOD=3.57; Table). We also found 4 peaks suggestive of linkage with other carotid traits (Table). There are many genes of interest underlying these peaks with previous association with vascular disease, and fine-mapping the associations will require further refinement via sequence analysis. This is the first study to show that genetics appear to play a very strong role in determining variation in carotid artery traits in families with exceptionally long-lived members.

Variants regulating ZBTB4 are associated with age-at-onset of Alzheimer's disease.

The identification of novel genetic modifiers of age-at-onset (AAO) of Alzheimer's disease (AD) could advance our understanding of AD and provide novel therapeutic targets. A previous genome scan for modifiers of AAO among families affected by early-onset AD caused by the PSEN2 N141I variant identified 2 loci with significant evidence for linkage: 1q23.3 and 17p13.2. Here, we describe the fine-mapping of these 2 linkage regions, and test for replication in 6 independent datasets. By fine-mapping these linkage signals in a single large family, we reduced the linkage regions to 11% their original size and nominated 54 candidate variants. Among the 11 variants associated with AAO of AD in a larger sample of Germans from Russia, the strongest evidence implicated promoter variants influencing NCSTN on 1q23.3 and ZBTB4 on 17p13.2. The association between ZBTB4 and AAO of AD was replicated by multiple variants in independent, trans-ethnic datasets. Our results show association between AAO of AD and both ZBTB4 and NCSTN. ZBTB4 is a transcriptional repressor that regulates the cell cycle, including the apoptotic response to amyloid beta, while NCSTN is part of the gamma secretase complex, known to influence amyloid beta production. These genes therefore suggest important roles for amyloid beta and cell cycle pathways in AAO of AD.

Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family

Background and aimsHypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41–0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). MethodsWe utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). ResultsWe did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. ConclusionsTaken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs.

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.

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.

Association of a synonymous SCN1B variant affecting splicing efficiency with Benign Familial Infantile Epilepsy (BFIE).

Benign Familial Infantile Epilepsy (BFIE) is clinically characterized by clusters of brief partial seizures progressing to secondarily generalized seizures with onset at the age of 3-7 months and with favorable outcome. PRRT2 mutations are the most common cause of BFIE, and found in about 80% of BFIE families. In this study, we analyzed a large multiplex BFIE family by linkage and whole exome sequencing (WES) analyses. Genome-wide linkage analysis revealed significant evidence for linkage in the chromosomal region 19p12-q13 (LOD score 3.48). Mutation screening of positional candidate genes identified a synonymous SCN1B variant (c.492T>C, p.Tyr164Tyr) affecting splicing by the removal of a splicing silencer sequence, shown by in silico analysis, as the most likely causative mutation. In addition, the PRRT2 frameshift mutation (c.649dupC/p.Arg217Profs*8) was observed, showing incomplete, but high segregation with the phenotype. Invitro splicing assay of SCN1B expression confirmed the in silico findings showing a splicing imbalance between wild type and mutant exons. Herein, the involvement of the SCN1B gene in the etiology of BFIE, contributing to the disease phenotype as a modifier or part of an oligogenic predisposition, is shown for the first time.

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 ...

Abstract P109: Detection of Haplotypes Underlying a Coronary Artery Calcification Linkage Peak in the Family Heart Study

Coronary artery calcification (CAC) is the buildup of calcium deposits in the arteries leading to the heart, and is an indicator of atherosclerosis. CAC is known to have a genetic component, and a genome-wide linkage screen in the Family Heart Study identified significant evidence of linkage on chromosome 9 in the area near rs13293430, but no common variant in the linkage region showed significant evidence of association. Linkage screens attempt to identify covariance due to common ancestry at a genomic locus. This is robust to the presence of rare variation or multiple variants in a region, but is unable to identify the genomic feature causing the signal and additional research is needed to identify potential causative variants. Pairs of individuals who have inherited a locus from a common ancestor will share an identical sequence of alleles (a haplotype) within the region. To identify haplotypes influencing the trait in the region, a mixed effects model was used. CAC was modeled as a trait influenced by polygenic effects and locus-specific haplotype effects. This model has the benefit of jointly estimating the effect of each haplotype while separating the haplotype effect from the background polygenic effect. From the study, 2,687 individuals of European descent from 508 pedigrees with CAC scores were genotyped on the Illumina Human 1M-DuoV3 single nucleotide polymorphisms (SNP) array. Of these, 180 individuals from 23 pedigrees were for subsequent analysis due to membership in a pedigree contributing to the linkage signal. CAC scores were determined by cardiac CT scan and adjusted for age, sex, and principal components before analysis. Phased haplotypes were generated for 906,856 common SNPs across the genome using SHAPEIT. The region between 25Mb and 35Mb (3,500 SNPs) was divided into 250kb sections, and within each section haplotypes were created based on 24 evenly spaced SNPs. Statistical significance for each region was determined by likelihood ratio test. Haplotype analysis identified two regions showing strong evidence of association (p&amp;lt;10 -7 ) with CAC. The region 28-28.25Mb is located completely within the gene LINGO2, which has been associated with BMI and cholesterol. The region 27.5-27.75Mb contains MOBKL2B, IFNK and C9orf72. Additional work will be needed to validate haplotypes used in the model and identify the particular haplotype influencing the trait.