Logarithm Of The Odds Score Research Articles

Genetic dissection of Meloidogyne incognita resistance genes based on VIGS functional analysis in Cucumis metuliferus

The southern root-knot nematode, Meloidogyne incognita, is a highly serious plant parasitic nematode species that causes significant economic losses in various crops, including cucumber (Cucumis sativus L.). Currently, there are no commercial cultivars available with resistance to M. incognita in cucumber. However, the African horned melon (Cucumis metuliferus Naud.), a semi-wild relative of cucumber, has shown high resistance to M. incognita. In this study, we constructed an ultrahigh-density genetic linkage bin-map using low-coverage sequences from an F2 population generated through the cross between C. metuliferus inbred lines CM3 and CM27. Finally, we identified a QTL (quantitative trait locus, QTL3.1) with a LOD (logarithm of the odds) score of 3.84, explaining 8.4% of the resistance variation. Subsequently, by combining the results of qPCR (quantitative PCR) and VIGS (virus-induced gene silencing), we identified two genes, EVM0025394 and EVM0006042, that are potentially involved in the resistance to M. incognita in CM3. The identification of QTLs and candidate genes in this study serve as a basis for further functional analysis and lay the groundwork for harnessing this resistance trait.

Deciphering the genetic architecture of β-glucan content in oats (Avena sativa L.) through QTL mapping

Oat is a cereal grain grown for human and animal nutrition. It is known for its high dietary fibre content, phytochemicals, and nutritional value. The primary component of oat fibre is β-glucan, a group of polysaccharides comprising mixed-linkage (1,3) (1,4)-D-glucose units. The β-glucan concentrations of oat cultivars usually range from 3 to 6% and are considered a polygenic trait controlled by multiple genes with additive effects. The primary goal of this study was to identify quantitative trait loci (QTLs) for β-glucan content. Two contrasting parents for β-glucan content, OL10 (5.8%) and OL11 (0.8%), were selected from 91 germplasm lines, and an F2:4 mapping population was generated for QTL mapping. Five genotypes with the highest levels of β-glucan content were observed. The QTLs affecting β-glucan content were identified using QTL cartographer, employing single marker analysis (SMA) and composite interval mapping (CIM). Two putative QTL regions were identified, one on linkage group (LG) 1 and the other on LG 4, with LOD (logarithm of the odds) scores of 3.7 and 4.3, respectively, explaining 31 and 33% of the phenotypic variation. The information generated is important in identifying the genomic regions responsible for β-glucan content in oats.

Genetic Mapping for QTL Associated with Seed Nickel and Molybdenum Accumulation in the Soybean 'Forrest' by 'Williams 82' RIL Population.

Understanding the genetic basis of seed Ni and Mo is essential. Since soybean is a major crop in the world and a major source for nutrients, including Ni and Mo, the objective of the current research was to map genetic regions (quantitative trait loci, QTL) linked to Ni and Mo concentrations in soybean seed. A recombinant inbred line (RIL) population was derived from a cross between 'Forrest' and 'Williams 82' (F × W82). A total of 306 lines was used for genotyping using 5405 single nucleotides polymorphism (SNP) markers using Infinium SNP6K BeadChips. A two-year experiment was conducted and included the parents and the RIL population. One experiment was conducted in 2018 in North Carolina (NC), and the second experiment was conducted in Illinois in 2020 (IL). Logarithm of the odds (LOD) of ≥2.5 was set as a threshold to report identified QTL using the composite interval mapping (CIM) method. A wide range of Ni and Mo concentrations among RILs was observed. A total of four QTL (qNi-01, qNi-02, and qNi-03 on Chr 2, 8, and 9, respectively, in 2018, and qNi-01 on Chr 20 in 2020) was identified for seed Ni. All these QTL were significantly (LOD threshold > 2.5) associated with seed Ni, with LOD scores ranging between 2.71-3.44, and with phenotypic variance ranging from 4.48-6.97%. A total of three QTL for Mo (qMo-01, qMo-02, and qMo-03 on Chr 1, 3, 17, respectively) was identified in 2018, and four QTL (qMo-01, qMo-02, qMo-03, and qMo-04, on Chr 5, 11, 14, and 16, respectively) were identified in 2020. Some of the current QTL had high LOD and significantly contributed to the phenotypic variance for the trait. For example, in 2018, Mo QTL qMo-01 on Chr 1 had LOD of 7.8, explaining a phenotypic variance of 41.17%, and qMo-03 on Chr 17 had LOD of 5.33, with phenotypic variance explained of 41.49%. In addition, one Mo QTL (qMo-03 on Chr 14) had LOD of 9.77, explaining 51.57% of phenotypic variance related to the trait, and another Mo QTL (qMo-04 on Chr 16) had LOD of 7.62 and explained 49.95% of phenotypic variance. None of the QTL identified here were identified twice across locations/years. Based on a search of the available literature and of SoyBase, the four QTL for Ni, identified on Chr 2, 8, 9, and 20, and the five QTL associated with Mo, identified on Chr 1, 17, 11, 14, and 16, are novel and not previously reported. This research contributes new insights into the genetic mapping of Ni and Mo, and provides valuable QTL and molecular markers that can potentially assist in selecting Ni and Mo levels in soybean seeds.

The effect of ascertainment on penetrance estimates for rare variants: Implications for establishing pathogenicity and for genetic counselling.

Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.

Identification of genomic loci regulating platelet plasminogen activator inhibitor-1 in mice

BackgroundPlasminogen activator inhibitor-1 (PAI-1, Serpine1) is an important circulating fibrinolysis inhibitor. PAI-1 exists in 2 pools, packaged within platelet α-granules and freely circulating in plasma. Elevated plasma PAI-1 levels are associated with cardiovascular disease. However, little is known about the regulation of platelet PAI-1 (pPAI-1). ObjectivesWe investigated the genetic control of pPAI-1 levels in mice and humans. MethodsWe measured pPAI-1 antigen levels via enzyme-linked immunosorbent assay in platelets isolated from 10 inbred mouse strains, including LEWES/EiJ (LEWES) and C57BL/6J (B6). LEWES and B6 were crossed to produce the F1 generation, B6LEWESF1. B6LEWESF1 mice were intercrossed to produce B6LEWESF2 mice. These mice were subjected to genome-wide genetic marker genotyping followed by quantitative trait locus analysis to identify pPAI-1 regulatory loci. ResultsWe identified differences in pPAI-1 between several laboratory strains, with LEWES having pPAI-1 levels more than 10-fold higher than those in B6. Quantitative trait locus analysis of B6LEWESF2 offspring identified a major pPAI-1 regulatory locus on chromosome 5 from 136.1 to 137.6 Mb (logarithm of the odds score, 16.2). Significant pPAI-1 modifier loci on chromosomes 6 and 13 were also identified. ConclusionIdentification of pPAI-1 genomic regulatory elements provides insights into platelet/megakaryocyte-specific and cell type–specific gene expression. This information can be used to design more precise therapeutic targets for diseases where PAI-1 plays a role.

The association between VSX1 exon3 gene variants and keratoconus in Malaysian patients.

This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients. A case-control study was done on 42 keratoconus cases, 127 family member controls, and 96 normal controls. Three gene variants, p.A182A, p.P237P, and p.R217H showed significant associations with keratoconus (P < 0.05). While p.A182A and p.P227P were more prevalent than in the family and normal controls (OR 3.14-4.05), the reverse was observed with p.R217H (OR 0.086-1.59). With Haploview analysis, p.A182A and p.P237P were shown to be in linkage disequilibrium (LD) (LOD (logarithm of the odds score) score of 2.0, r2 of 0.957, and 95% confidence interval (CI) of 0.96-1.00). The study results suggest that the p.A182A and p.P237P variants could have contributed to the development of keratoconus in some Malaysians and that these two variants are likely to be co-inherited. In contrast, the p.R217H variant appeared to confer some protection against the development of keratoconus.

Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity but Not Cardiomyocyte Proliferation.

Identifying genetic variants that affect the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity after permanent coronary artery ligation compared with infarcted DBA/2J (D2J) mice. Cardiomyocyte cell cycle activity after infarction was monitored in D2J, (D2J×B6N)-F1, and (D2J×B6N)-F1×D2J backcross mice by means of bromodeoxyuridine or 5-ethynyl-2'-deoxyuridine incorporation using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus analysis, fine scale genetic mapping, whole exome sequencing, and RNA sequencing analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype. (D2J×B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar compared with D2J mice (0.798±0.09% versus 0.056±0.004%; P<0.001). Quantitative trait locus analysis of (D2J×B6N)-F1×D2J backcross mice revealed that the gene responsible for differential S-phase activity was located on the distal arm of chromosome 3 (logarithm of the odds score=6.38; P<0.001). Additional genetic and molecular analyses identified 3 potential candidates. Of these, Tnni3k (troponin I-interacting kinase) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of TNNI3K in a D2J genetic background results in elevated cardiomyocyte S-phase activity after injury. Cardiomyocyte S-phase activity in both Tnni3k-expressing and Tnni3k-nonexpressing mice results in the formation of polyploid nuclei. These data indicate that Tnni3k expression increases the level of cardiomyocyte S-phase activity after injury.

Resolving the recombination pattern of 38 X-STRs from Chinese Han three-generation pedigrees

X-chromosomal markers have been proved as a useful tool for solving complex kinship cases due to its sex-linked inheriting feature. Among these markers, tightly linked X-STR clusters forming haplotypes are highly informative. The analysis of the haplotypes requires determination of linkage disequilibrium. In this study, genetic linkage, recombination fractions and mutation rates of 38 X-STR loci in 177 three-generation pedigrees were investigated. Genetic linkage analysis and calculation of recombination fractions were performed within each pair of markers and clusters. Then mutation rates were calculated. The results showed that, a) 22 recombination events happened within the tightly linked X-STR clusters, which span<1.0 Mb; b) significantly linked marker pairs were observed with the LOD (logarithm of the odds) scores > 2.0 (2.0104 to 54.8316); c) the average mutation rate of the 38 X-STR loci was 1.32 × 10−3 per meiosis in the Chinese Han population, with DXS10135 and DXS8377 presenting notably high mutation rate (6.5 × 10−3). Our results confirmed that meiotic recombination was not a simple function of physical distance, so that whether recombination occurred at the closely clustered X-STRs or not should be assumed cautiously considering the stability of haplotypes in inheritance process for kinship analysis. This study supplemented the existing database and laid an experimental foundation for the future study on genetic characteristics, recombination, and mutation of the X-STRs.

A novel leaky splice variant in centromere protein J (CENPJ)-associated Seckel syndrome.

Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but ∼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T>C) in CENPJ (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of CENPJ in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known CENPJ function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of CENPJ-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.

Novel Positional Candidate Gene for Gait Speed Change in Older Adults: The Long Life Family Study

Older adults living alone are at higher risk of mortality, morbidity and healthcare utilization. As more older adults live alone, Emergency Department (ED) admissions could rapidly increase, particularly among those with multimorbidity. We studied the association of living alone on ED admissions among older adults with multimorbidity. We used data from 16,785 older adults of the population-based Singapore Chinese Health Study (mean age: 73 years, range: 61-96 years) who were interviewed in 2014-2016 for living arrangements and medical history. Participants were followed-up for one year on ED admission outcomes (number of admissions, inpatient days and hospitalization costs). We used multivariable logistic regression to study the association between living alone and ED admission, and ran two-part models (probit & generalised linear model) to estimate the association of living alone on inpatient days and hospitalization cost. We found that compared to living with others, living alone was associated with a higher odds of ED admissions [Odds Ratio (OR) 1.28, 95% Confidence Interval (CI) 1.08-1.51)], longer inpatient days (+0.61, 95% CI 0.25-0.97) and higher hospitalization costs (+322 USD, 95% CI 54-591). Compared to those living with others without multimorbidity, living alone with multimorbidity was associated with higher odds of ED admission (OR 1.64 95% CI 1.33-2.03), longer inpatient days (+0.73, 95% CI 0.29-1.17) and higher hospitalization costs (+567 USD, 95% CI 230-906). In conclusion, living alone is associated with higher odds of ED admission, longer inpatient days and higher hospitalization costs among older adults, particularly among those with multimorbidity.

Novel Positional Candidate Gene for Gait Speed Change in Older Adults: The Long Life Family Study

Research has shown cognitive ability in older age is associated with activity engagement, but little is known about what psychological mechanisms are linking the two constructs. This study investigates an emotional pathway, in which affective states mediate the temporal associations between momentary working memory and momentary activities in older age. We examined data from 153 healthy older adults aged 65 to 91 who completed a smartphone-based ambulatory assessment survey seven times a day over 15 days. In each assessment point, participants reported their momentary activities (e.g., social activities, mentally stimulating activities) and affective states (i.e., positive affect, negative affect) and took a working memory task. Initial results suggest that during an approximate time period of six hours (i.e., across three assessment points), working memory performance influences subsequent likelihood of social activity engagement. Moreover, positive affect mediates this temporal association. Results will be discussed in the context of cognitive aging research.

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.

Genome-Wide Linkage Study Meta-Analysis of Male Sexual Orientation

Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait.

Genome-Wide Linkage Analysis Identifies a Novel Locus for Grip Strength: The Long Life Family Study

Grip strength declines with aging, is an indicator of overall health, and predicts mortality among older adults. Herein, we quantified the genetic contributions to grip strength among 4534 individuals, belonging to 574 families in the Long Life Family Study (age 70.3 ± 15.7, range 24–110 years; 56% women). Grip strength was measured using a handheld dynamometer, and the maximum value of two trials in the stronger hand was used. Quantitative trait linkage analysis was completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores >3.0 indicating genome-wide significance. Linkage analysis in the top 10% of families contributing to LOD scores was also performed to allow for heterogeneity among families (HLOD). All analyses were adjusted for age, sex, height and field center. Grip strength was lower per one year of older age (β: -0.34 ± 0.01kg, p <0.01), and overall: 24.3% of men and 19.3% of women had “low” grip strength according to European Working Group on Sarcopenia definitions. Grip strength was highly heritable (h2 = 0.37, p<0.05). We identified a potentially novel locus for grip strength on chromosome 18p (LOD 3.18) with 26 families contributing to this linkage peak (HLOD = 10.94). Deep sequencing of the chromosome 18 region may yield fundamental insight on the biology of muscle weakness with aging, and may help identify novel therapeutic targets for treatment and prevention of this common condition.

VEGFA Promoter Polymorphisms rs699947 and rs35569394 Are Associated With the Risk of Anterior Cruciate Ligament Ruptures Among Indian Athletes: A Cross-sectional Study.

Background:Associations of genetic variants within certain fibril-forming genes have previously been observed with anterior cruciate ligament (ACL) injuries. Evidence suggests a significant role of angiogenesis-associated cytokines in remodeling the ligament fibril matrix after mechanical loading and maintaining structural and functional integrity of the ligament. Functional polymorphisms within the vascular endothelial growth factor A (VEGFA) gene have emerged as plausible candidates owing to their role in the regulation of angiogenic responses.Hypothesis:VEGFA promoter polymorphisms rs699947 and rs35569394 are associated with ACL injury risk among athletes.Study Design:Cross-sectional study; Level of evidence, 3.Methods:A total of 90 Indian athletes with radiologically confirmed or surgically proven isolated ACL tears and 76 matched-control athletes were selected for the present cross-sectional genetic association study. Oral mouthwash samples were collected from all the case and control athletes and genotyped for VEGFA rs699947 and rs35569394 using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.Results:The A allele (rs699947) was significantly overrepresented in the ACL group (C vs A allele: odds ratio [OR], 1.68 [95% CI, 1.08-2.60]; P = .021) (CC vs CA + AA: OR, 2.69 [95% CI, 1.37-5.26]; P = .004). There was a greater frequency of the AA genotype in the ACL group in comparison with the control group (OR, 3.38 [95% CI, 1.23-9.28]; P = .016) when only male athletes were compared. Likewise, there was a greater frequency of the I allele (rs35569394) in the ACL group (D vs I allele: OR, 1.64 [95% CI, 1.06-2.55]; P = .025) (DD vs ID + II: OR, 2.61 [95% CI, 1.31-5.21]; P = .006). The A-I haplotype was overrepresented in the ACL group compared with the control group (OR, 1.68 [95% CI, 1.08-2.60]; χ2 = 5.320; P = .021), and both the polymorphisms were found to be in complete linkage disequilibrium (r 2 = 0.929; logarithm of the odds score = 63.74; D′ = 1.0). Female athletes did not show any difference in genotype or allele frequency.Conclusion:This is the first study to investigate the association of VEGFA promoter polymorphisms in ACL tears among Indian athletes. Increased frequencies of the A allele (rs699947) and I allele (rs35569394) were observed in the ACL group. These results suggest that sequence variants in the VEGF gene are associated with ACL injury risk among athletes. Further research with long-term follow-ups measuring VEGF expression levels during recovery is warranted to establish its role in ACL injuries and healing.

Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region

Strabismus is a common condition, affecting 1%–4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no...

Dissection of quantitative trait loci for root characters and day length sensitivity in SynOpDH wheat (Triticum aestivum L.) bi-parental mapping population

AbstractThe genetics of the root system is still not dissected for wheat and lack of knowledge prohibits the use of marker-assisted selection in breeding. To understand the genetic mechanism of root development, Synthetic W7984 × Opata M85 doubled-haploid (SynOpDH) mapping population was evaluated for root and shoot characteristics in PVC tubes until maturity. Two major quantitative trait loci (QTLs) for total root biomass were detected on homoeologous chromosomes 2A and 2D with logarithm of the odds scores between 6.25–10.9 and 11.8–20.86, and total phenotypic effects between 12.7–17.7 and 26.6–40.04% in 2013 and 2014, respectively. There was a strong correlation between days to anthesis and root and shoot biomass accumulation (0.50–0.81). The QTL for biomass traits on chromosome 2D co-locates with QTL for days to anthesis. The effect of extended vegetative growth, caused by photoperiod sensitivity (Ppd) genes, on biomass accumulation was always hypothesized, this is the first study to genetically support this theory.

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.

Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature.

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole‐exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four‐generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2‐3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2‐3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.

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.