Linkage Scan Research Articles

Novel truncation mutations in MYRF cause autosomal dominant high hyperopia mapped to 11p12\u2013q13.3

High hyperopia is a common and severe form of refractive error. Genetic factors play important roles in the development of high hyperopia but the exact gene responsible for this condition is mostly unknown. We identified a large Chinese family with autosomal dominant high hyperopia. A genome-wide linkage scan mapped the high hyperopia to chromosome 11p12–q13.3, with maximum log of the odds scores of 4.68 at theta = 0 for D11S987. Parallel whole-exome sequencing detected a novel c.3377delG (p.Gly1126Valfs*31) heterozygous mutation in the MYRF gene within the linkage interval. Whole-exome sequencing in other 121 probands with high hyperopia identified additional novel mutations in MYRF within two other families: a de novo c.3274_3275delAG (p.Leu1093Profs*22) heterozygous mutation and a c.3194+2T>C heterozygous mutation. All three mutations are located in the C-terminal region of MYRF and are predicted to result in truncation of that portion. Two patients from two of the three families developed angle-closure glaucoma. These three mutations were present in neither the ExAC database nor our in-house whole-exome sequencing data from 3280 individuals. No other truncation mutations in MYRF were detected in the 3280 individuals. Knockdown of myrf resulted in small eye size in zebrafish. These evidence all support that truncation mutations in the C-terminal region of MYRF are responsible for autosomal dominant high hyperopia in these families. Our results may provide useful clues for further understanding the functional role of the C-terminal region of this critical myelin regulatory factor, as well as the molecular pathogenesis of high hyperopia and its associated angle-closure glaucoma.

Genome wide linkage scan for autoimmune thyroid disease susceptibility loci in multiplex Tunisian family.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Linkage analysis revealed risk loci on 6p21 and 18p11.2-q11.2 in familial colon and rectal cancer, respectively

Colorectal cancer (CRC) is one of the major cancer types in the western world including Sweden. However, known genetic risk factors could only explain a limited part of heritability of the disease. Moreover, colon and rectal cancers are habitually discussed as one entity, colorectal cancer, although different carcinogenesis has been recognized. A genome-wide linkage scan in 32 colon- and 56 rectal cancer families from Sweden was performed based on 475 non-FAP/HNPCC patients genotyped using SNP arrays. A maximum HLOD of 2.50 at locus 6p21.1-p12.1 and a HLOD of 2.56 at 18p11.2 was obtained for colon and rectal cancer families, respectively. Exome sequencing over the regions of interest in 12 patients from six families identified 22 and 25 candidate risk variants for colon and rectal cancer, respectively. Haplotype association analysis in the two regions was carried out between additional 477 familial CRC cases and 4780 controls and suggested candidate haplotypes possibly associated with CRC risk. This study suggested two new linkage regions for colon cancer and rectal cancer with candidate predisposing variants. Further studies are required to elucidate the pathogenic mechanism of these regions and to pinpoint the causative genes.

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.

Identification of Chromosomal Regions Linked to Diabetic Nephropathy: A Meta-Analysis of Genome-Wide Linkage Scans

Diabetic nephropathy (DN) has become a serious public health problem. Genetic factors are involved in the pathogenesis of DN, but the exact mode of inheritance is still unknown. Genome-wide linkage scans (GWLS) have produced inconclusive or inconsistent results. In an effort to test consistency and provide more conclusive results, we applied a heterogeneity-based genome search meta-analysis (HEGESMA) to GWLS regarding DN. We combined results from eight GWLS in the primary analysis and nine GWLS for a conditional analysis about DN for both diabetes types, as well as in each type of diabetes and ethnicity in subgroup analyses. HEGESMA identified cytogenetic locations that rank highly on average in terms of linkage statistics across multiple genome scans, taking into consideration the magnitude of heterogeneity of the results between scans. Main analyses: Our meta-analysis identified 13 cytogenetic locations (bins) with statistical significance (Prank ≤ 0.05), 11 of which were significant in both weighted and unweighted analyses located on chromosomes 1q, 3q, 4p, 5q, 7q, 15q, 16p, 17q, 19q, and 22p. In addition, four novel regions (5q11.2-5q14.3, 5q23.2-5q34, 17q24.3-17q25.3, and 22q12.3-22q13.3) were identified. Seven bins on chromosomes 4p, 5q, 7q, 15q, 22p, and 22q were common between both types of diabetes and in all subgroup analyses, in addition 5q14.3-5q23.2 was significant across all analyses. Conditional analyses: meta-analysis identified nine different cytogenetic locations, among which 7p22.3-7p15.3 was significant only in type 2 diabetes mellitus conditional analysis. Ethnicity subgroup analyses identified 11 different cytogenetic locations, 5 out of which are novel findings. However, none of the chromosomal regions reached genome-wide statistical significance (Prank < 0.00042). This meta-analysis provides evidence for linkage for nine novel cytogenetic regions that should be further investigated for genes that confer susceptibility to DN.

Two Novel Candidate Genes for Insulin Secretion Identified by Comparative Genomics of Multiple Backcross Mouse Populations.

To identify novel disease genes for type 2 diabetes (T2D) we generated two backcross populations of obese and diabetes-susceptible New Zealand Obese (NZO/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Subsequent whole-genome linkage scans revealed 30 novel quantitative trait loci (QTL) for T2D-associated traits. The strongest association with blood glucose [12 cM, logarithm of the odds (LOD) 13.3] and plasma insulin (17 cM, LOD 4.8) was detected on proximal chromosome 7 (designated Nbg7p, NZO blood glucose on proximal chromosome 7) exclusively in the NZOxC3H crossbreeding, suggesting that the causal gene is contributed by the C3H genome. Introgression of the critical C3H fragment into the genetic NZO background by generating recombinant congenic strains and metabolic phenotyping validated the phenotype. For the detection of candidate genes in the critical region (30-46 Mb), we used a combined approach of haplotype and gene expression analysis to search for C3H-specific gene variants in the pancreatic islets, which appeared to be the most likely target tissue for the QTL. Two genes, Atp4a and Pop4, fulfilled the criteria from our candidate gene approaches. The knockdown of both genes in MIN6 cells led to decreased glucose-stimulated insulin secretion, indicating a regulatory role of both genes in insulin secretion, thereby possibly contributing to the phenotype linked to Nbg7p In conclusion, our combined- and comparative-cross analysis approach has successfully led to the identification of two novel diabetes susceptibility candidate genes, and thus has been proven to be a valuable tool for the discovery of novel disease genes.

Genome-wide linkage scan for loci influencing plasma triglyceride levels

We conducted a genome-wide linkage scan to detect loci that influence the levels of fasting triglycerides in plasma. Fasting triglyceride levels were available at 4 time points (visits), 2 pre- and 2 post-fenofibrate intervention. Multipoint identity-by-descent (MIBD) matrices were derived from genotypes using IBDLD. Variance-component linkage analyses were then conducted using SOLAR (Sequential Oligogenic Linkage Analysis Routines). We found evidence of linkage (logarithm of odds [LOD] ≥3) at 5 chromosomal regions with triglyceride levels in plasma. The highest LOD scores were observed for linkage to the estimated genetic value (additive genetic component) of the log-normalized triglyceride levels in plasma. Our results suggest that a chromosome 10 locus at 37 cM (LODpre = 3.01, LODpost = 3.72) influences fasting triglyceride levels in plasma regardless of the fenofibrate intervention, and that loci in chromosomes 1 at 170 cM and 4 at 24 cM ceases to affect the triglyceride levels when fenofibrate is present, while the regions in chromosomes 6 at 136 to 162 cM and 11 at 39 to 40 cM appear to influence triglyceride levels in response to fenofibrate.

Fine-mapping analysis of a chromosome 2 region linked to resistance to Mycobacterium tuberculosis infection in Uganda reveals potential regulatory variants.

Tuberculosis (TB) is a major public health burden worldwide, and more effective treatment is sorely needed. Consequently, uncovering causes of resistance to Mycobacterium tuberculosis (Mtb) infection is of special importance for vaccine design. Resistance to Mtb infection can be defined by a persistently negative tuberculin skin test (PTST–) despite living in close and sustained exposure to an active TB case. While susceptibility to Mtb is, in part, genetically determined, relatively little work has been done to uncover genetic factors underlying resistance to Mtb infection. We examined a region on chromosome 2q previously implicated in our genomewide linkage scan by a targeted, high-density association scan for genetic variants enhancing PTST– in two independent Ugandan TB household cohorts (n = 747 and 471). We found association with SNPs in neighboring genes ZEB2 and GTDC1 (peak meta p = 1.9 × 10−5) supported by both samples. Bioinformatic analysis suggests these variants may affect PTST– by regulating the histone deacetylase (HDAC) pathway, supporting previous results from transcriptomic analyses. An apparent protective effect PTST– against body-mass wasting suggests a link between resistance to Mtb infection and healthy body composition. Our results provide insight into how humans may escape latent Mtb infection despite heavy exposure.

Novel caries loci in children and adults implicated by genome-wide analysis of families

BackgroundDental caries is a common chronic disease among children and adults alike, posing a substantial health burden. Caries is affected by multiple genetic and environmental factors, and prior studies have found that a substantial proportion of caries susceptibility is genetically inherited.MethodsTo identify such genetic factors, we conducted a genome-wide linkage scan in 464 extended families with 2616 individuals from Iowa, Pennsylvania and West Virginia for three dental caries phenotypes: (1) PRIM: dichotomized as zero versus one or more affected primary teeth, (2) QTOT1: age-adjusted quantitative caries measure for both primary and permanent dentitions including pre-cavitated lesions, and (3) QTOT2: age-adjusted quantitative caries excluding pre-cavitated lesions. Genotyping was conducted for approximately 600,000 SNPs on an Illumina platform, pruned to 127,511 uncorrelated SNPs for the analyses reported here.ResultsMultipoint non-parametric linkage analyses generated peak LOD scores exceeding 2.0 for eight genomic regions, but no LOD scores above 3.0 were observed. The maximum LOD score for each of the three traits was 2.90 at 1q25.3 for PRIM, 2.38 at 6q25.3 for QTOT1, and 2.76 at 5q23.3 for QTOT2. Some overlap in linkage regions was observed among the phenotypes. Genes with a potential role in dental caries in the eight chromosomal regions include CACNA1E, LAMC2, ALMS1, STAMBP, GXYLT2, SLC12A2, MEGF10, TMEM181, ARID1B, and, as well as genes in several immune gene families. Our results are also concordant with previous findings from association analyses on chromosomes 11 and 19.ConclusionsThese multipoint linkage results provide evidence in favor of novel chromosomal regions, while also supporting earlier association findings for these data. Understanding the genetic etiology of dental caries will allow designing personalized treatment plans based on an individual’s genetic risk of disease.

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.

Genome-wide scan for circulating vascular adhesion protein-1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis.

Aims/IntroductionVascular adhesion protein‐1 (VAP‐1) is a membrane‐bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP‐1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP‐1 levels.Materials and MethodsWe carried out a genomic‐wide linkage scan for the quantitative trait locus of circulating VAP‐1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single‐nucleotide polymorphisms.ResultsThe estimated heritability of circulating VAP‐1 levels is high (h 2 = 69%). The most significant quantitative trait locus for circulating VAP‐1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 × 10−6) in females. Regional single‐nucleotide polymorphism fine mapping within a 1‐unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 × 10−6). Knockdown of MACROD2 significantly suppressed VAP‐1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD2 expression was found to be positively associated with VAP‐1 in human visceral adipose tissue.Conclusion MACROD2 is a potential genetic determinant of serum VAP‐1 levels, probably through transcriptional regulation of adipogenesis.

A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings.

To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in PITX2 in the family. Patients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to verify the expression of the pathogenic gene. Genome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G) that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family. Our findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found.

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.

T55 - The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression

While the prevalence of major depression is known to be elevated amongst cannabis users, the causes of this comorbidity are not clear. Here we investigate the role of genetics in this relationship and identify genomic loci linked to these traits. Using a sample of Mexican American extended families (n=1,284), we use variance decomposition methods to establish the degree of genetic correlation between cannabis use and major depression. Genome-wide univariate and bivariate linkage scans are conducted to localize the chromosomal regions influencing these traits and the comorbidity observed between them. Both major depression (h2=0.349, p=1.06x10-5, SE=0.100) and cannabis use (h2=0.614, p=1.00x10-6, SE=0.151) are heritable traits, and there is significant genetic correlation between the two (ρg=0.424, p=0.0364, SE=0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 (LOD=3.144 at 2cM), with a suggestive peak for cannabis use on chromosome 21 (LOD=2.123 at 37cM). A significant pleiotropic linkage peak influencing both major depression and cannabis use was identified on chromosome 11, using a bivariate model (LOD=3.229 at 112cM). This location spans the NCAM1-TTC12-ANKK1-DRDR2 gene cluster. Follow-up of this pleiotropic signal provided tentative evidence implicating a rare SNP 20kb upstream of NCAM1 (s7932341); with peak-wide significant bivariate association with cannabis use and major depression (p=3.10x10-5). We show that genetic influences play an important role in the comorbidity between cannabis use and major depression.Specifically, we identify a pleiotropic locus on chromosome 11, spanning the NCAM1-TTC12-ANKK1-DRDR2 gene cluster, which has been previously implicated in both addiction and depression research.

GRONS: a comprehensive genetic resource of nicotine and smoking.

Nicotine, the primary psychoactive component in tobacco, can exert a broad impact on both the central and peripheral nervous systems. During the past years, a tremendous amount of efforts has been put to exploring the molecular mechanisms underlying tobacco smoking related behaviors and diseases, and many susceptibility genes have been identified via various genomic approaches. For many human complex diseases, there is a trend towards collecting and integrating the data from genetic studies and the biological information related to them into a comprehensive resource for further investigation, but we have not found such an effort for nicotine addiction or smoking-related phenotypes yet. To collect, curate, and integrate cross-platform genetic data so as to make them interpretable and easily accessible, we developed Genetic Resources Of Nicotine and Smoking (GRONS), a comprehensive database for genes related to biological response to nicotine exposure, tobacco smoking related behaviors or diseases. GRONS deposits genes from nicotine addiction studies in the following four categories, i.e. association study, genome-wide linkage scan, expression analysis on genes/proteins via high-throughput technologies, as well as single gene/protein-based experimental studies via literature search. Moreover, GRONS not only provides tools for data browse, search and graphical presentation of gene prioritization, but also presents the results from comprehensive bioinformatics analyses for the prioritized genes associated with nicotine addiction. With more and more genetic data and analysis tools integrated, GRONS will become a useful resource for studies focusing on nicotine addiction or tobacco smoking. Database URL: http://bioinfo.tmu.edu.cn/GRONS/

A combined linkage and association strategy identifies a variant near the GSTP1 gene associated with BMI in the Mexican population.

Obesity is a major public health concern in Mexico and worldwide. Although the estimated heritability is high, common variants identified by genome-wide association studies explain only a small proportion of this heritability. A combination of linkage and association strategies could be a more robust and powerful approach to identify other obesity-susceptibility variants. We thus sought to identify novel genetic variants associated with obesity-related traits in the Mexican population by combining these methods. We performed a genome-wide linkage scan for body mass index (BMI) and other obesity-related phenotypes in 16 Mexican families using the Sequential Oligogenic Linkage Analysis Routines Program. Associated single-nucleotide polymorphisms (SNPs) were tested for associations in an independent cohort. Two suggestive BMI-linkage peaks (logarithm of odds ⩾1.5) were observed at chromosomal regions 11q13 and 13q22. Only rs614080 in the 11q13 region was significantly associated with BMI and related traits in these families. This association was also significant in an independent cohort of Mexican adults. Moreover, this variant was significantly associated with GSTP1 gene expression levels in adipose tissue. In conclusion, the rs614080 SNP near the GSTP1 gene was significantly associated with BMI and GSTP1 expression levels in the Mexican population.

Sex-specific linkage scans in opioid dependence.

Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6,000 single nucleotide polymorphism (SNP) markers were genotyped for 1,758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD = 3.29; point-wise P = 0.00005; empirical autosome-wide P = 0.042), which significantly differed from the linkage signal at the same location in EA women (empirical P = 0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD = 2.18), 104 cM on chromosome 11 (LOD = 1.85), and 60.9 cM on chromosome 16 (LOD = 1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD = 2.32), 152.9 cM on chromosome 6 (LOD = 1.86), 16.8 cM on chromosome 7 (LOD = 1.95), and 36.1 cM on chromosome 17 (LOD = 1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex-specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next-generation sequencing to search for genes that contribute to sex-specific differences in OD. © 2016 Wiley Periodicals, Inc.

Single nucleotide polymorphisms in an intergenic chromosome 2q region associated with tissue factor pathway inhibitor plasma levels and venous thromboembolism

Essentials Tissue factor pathway inhibitor (TFPI) regulates the blood coagulation cascade. We replicated previously reported linkage of TFPI plasma levels to the chromosome 2q region. The putative causal locus, rs62187992, was associated with TFPI plasma levels and thrombosis. rs62187992 was marginally associated with TFPI expression in human aortic endothelial cells. Click to hear Ann Gil's presentation on new insights into thrombin activatable fibrinolysis inhibitor SUMMARY: Background Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial thromboembolism and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes. Objectives To replicate the finding of the linkage region in an independent sample, and to identify the causal locus. Methods We first performed a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study, and replicated the finding of the linkage peak on chromosome 2q (LOD = 3.06). We next defined a follow-up region that included 112 603 single nucleotide polymorphisms (SNPs) under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and the Marseille Thrombosis Association (MARTHA) Study, a study of 1033 unrelated VTE patients. SNPs with false discovery rate q-values of < 0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene Study. Results and Conclusions One SNP, rs62187992, was associated with TFPI plasma levels in all three samples (β = + 0.14 and P = 4.23 × 10-6 combined; β = + 0.16 and P = 0.02 in the F5L Family Study; β = + 0.13 and P = 6.3 × 10-4 in the MARTHA Study; β = + 0.17 and P = 0.03 in the AtheroGene Study), and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio 0.90, P = 0.03) in the INVENT Consortium of > 7000 cases and their controls, and was marginally associated with TFPI expression (β = + 0.19, P = 0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated.

The genetic basis of the comorbidity between cannabis use and major depression.

While the prevalence of major depression is elevated among cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits and localize regions of the genome that segregate in families with cannabis use and major depression. Family-based univariate and bivariate genetic analysis. San Antonio, Texas, USA. Genetics of Brain Structure and Function study (GOBS) participants: 1284 Mexican Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses. Phenotypes of life-time history of cannabis use and major depression, measured using the semistructured MINI-Plus interview. Genotypes measured using ~1M single nucleotide polymorphisms (SNPs) on Illumina BeadChips. A subselection of these SNPs were used to build multi-point identity-by-descent matrices for linkage analysis. Both cannabis use [h2 =0.614, P=1.00×10-6 , standard error (SE)=0.151] and major depression (h2 =0.349, P=1.06×10-5 , SE=0.100) are heritable traits, and there is significant genetic correlation between the two (ρg =0.424, P=0.0364, SE=0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 [logarithm of the odds (LOD)=3.144 at 2centimorgans (cM)], with a suggestive peak for cannabis use on chromosome 21 (LOD=2.123 at 37cM). A significant pleiotropic linkage peak influencing both cannabis use and major depression was identified on chromosome 11 using a bivariate model (LOD=3.229 at 112cM). Follow-up of this pleiotropic signal identified a SNP 20kb upstream of NCAM1 (rs7932341) that shows significant bivariate association (P=3.10×10-5 ). However, this SNP is rare (seven minor allele carriers) and does not drive the linkage signal observed. There appears to be a significant genetic overlap between cannabis use and major depression among Mexican Americans, a pleiotropy that appears to be localized to a region on chromosome 11q23 that has been linked previously to these phenotypes.

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person’s ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14–q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1717-z) contains supplementary material, which is available to authorized users.