Polygenic Cause Research Articles

Genome-wide transcriptional profiling data from skin of chronic cutaneous lupus erythematosus (CCLE) patients.

Cutaneous features manifest as a wide range of clinically significant, and in many cases disfiguring and debilitating components of lupus erythematosus (LE). While the definitive etiology is in question, multifactorial and polygenic causes are likely to be involved in the production of the characteristic anti-nuclear autoantibody titers and immune cell infiltrates observed in chronic cutaneous LE (CCLE) [1–3]. There is significant overlap of patients with systemic and cutaneous manifestations of LE, which suggests shared pathways and genetic background between the two. We have employed genome-wide microarray technology along with pathway-based analyses to investigate transcriptional differences between lesional and non-lesional skin from CCLE patients to address existing gaps in knowledge regarding disease mechanisms in lupus [4].

Abstract 18262: Molecular Genetics of Familial Hypercholesterolemia in Israel Revisited

Background: In 1996, the first summary of molecular genetics of familial hypercholesterolemia (FH) in Israel was published (Reshef A, Hum Gen, 1996). Since then, new technology for mutation screening became available making genetic diagnosis easier more accurate, and more comprehensive. We performed systematic mutation screening of index cases of 68 pedigrees to reanalyze the profile of mutations among Israeli FH patients. Methods and results: In 68 individuals the entire coding region, promoter and intron-exon junctions of the LDLR and part of exon 26 of the APOB gene were screened for variants using High Resolution Melting, with Sanger sequencing of any identified melt shifts. Mutations of the LDLR gene were found in twenty-three patients (34% of the total) with seventeen different mutations . The most common mutation was p.(V827I) (47% of the detected mutations), not previously reported in Refech et al but reported to occur in patients from Russia. Three variants, two in exon 4 and one in the promoter region were not reported before; p.(C121S), p.(E140A) and c.-191 C>A. One patient carried the common APOB p.(R3527Q) mutation. 70% of the cohort were negative for an LDLR or APOB mutation. It was hypothesized that FH can be caused by an accumulation of LDL-C raising alleles each having a small contributive effect (Talmud et al., 2013). Using this published gene score method derived from twelve common LDL-C raising SNPs in eleven genes, the mean polygene score was significantly higher (p=0.03) among mutation negative Israeli FH patients compared with a European control population. Conclusion: We identified mutations in 30% of a new Israeli FH cohort. In these we found 3 novel LDLR mutations. The high prevalence of p.(V827I) likely reflects the change in demographics of the Israeli population since 1996 . In the remaining mutation free cohort, there is likely to be a polygenic cause of their elevated LDL-C and FH diagnosis. These data can help design a future strategy for early screening for FH in our population.

Genetic basis of human left-right asymmetry disorders.

Humans and other vertebrates exhibit left-right (LR) asymmetric arrangement of the internal organs, and failure to establish normal LR asymmetry leads to internal laterality disorders, including situs inversus and heterotaxy. Situs inversus is complete mirror-imaged arrangement of the internal organs along LR axis, whereas heterotaxy is abnormal arrangement of the internal thoraco-abdominal organs across LR axis of the body, most of which are associated with complex cardiovascular malformations. Both disorders are genetically heterogeneous with reduced penetrance, presumably because of monogenic, polygenic or multifactorial causes. Research in genetics of LR asymmetry disorders has been extremely prolific over the past 17 years, and a series of loci and disease genes involved in situs inversus and heterotaxy have been described. The review highlights the classification, chromosomal abnormalities, pathogenic genes and the possible mechanism of human LR asymmetry disorders.

The fine line between familial and polygenic hypercholesterolemia

Evaluation of: Talmud PJ, Shah S, Whittall R et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic hypercholesterolaemia: a case–control study. Lancet 381(9874), 1293–1301 (2013). Familial hypercholesterolemia (FH) is a common disorder caused by mutations in LDLR, APOB and PCSK9. However, many subjects with primary hypercholesterolemia did not demonstrate functional mutations in any of these genes. Genome-wide association studies have identified single nucleotide polymorphisms that influence the variability of LDL-C concentration. Talmud et al. have genotyped 12 common LDL cholesterol (LDL-C)-raising alleles in 640 patients with the clinical diagnosis of FH and in 3020 healthy subjects from the UK Whitehall II study. Approximately 50% of the FH patients did not possess a causative mutation and the mean weighted LDL-C gene score was significantly higher than in the controls, indicating a polygenic cause for their disorder. These results indicate t...

Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study

Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.

Gene expression in visceral and subcutaneous adipose tissue in overweight women

Excess weight and obesity are common health problems with multifactorial and polygenic causes. Abdominal or visceral obesity is associated with a higher risk of obesity related complications. The aim of the study was to evaluate differentially expressed genes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 overweight women undergoing elective laparoscopic cholecystectomy. Following expression profiling using microarrays, a set of 294 genes that exhibited differential expression between VAT and SAT was further analyzed to test the functional correlation of gene sets using the Gene Set Enrichment Analysis method. To confirm the functional pathways involved in differential expression between SAT and VAT, additional pathway analysis was done using the GeneGo MetaCore software and the Ingenuity Pathway Analysis. Ten differentially expressed genes were selected according to the microarray data, with seven exhibiting significant differential expression in the RT-PCR experiments. The data from this preliminary study suggest enrichment of inflammation and oxidative stress related pathways in VAT, while insulin homeostasis pathways as well as pathways pertaining to several growth factors are enriched in SAT.

The Autism Candidate Gene Neurobeachin Encodes a Scaffolding Protein Implicated in Membrane Trafficking and Signaling

Autism is a developmental disorder of the central nervous system characterized by impairments in social interaction, communication and restricted repetitive and stereotyped behavior. It is generally assumed that in most cases autism has a polygenic cause, but the pathogenesis is still unknown. Neurobeachin (NBEA) has recently been identified as a candidate gene for autism in a patient with a de novo chromosomal translocation and three patients with a monoallelic deletion. This multidomain scaffolding protein has been suggested to be involved in neuronal post-Golgi membrane traffic. Knockout of Nbea in two independent mouse models has demonstrated a role in neurotransmitter release and synaptic functioning. Knockdown in a cell line has shown a role as negative regulator of secretion of large dense-core vesicles (LDCVs) and haploinsufficiency in blood platelets results in dense granules with an aberrant morphology. A potential role in vesicle transport is further supported by a study of SEL-2, the C.elegans homologue of NBEA. This protein was identified as a negative regulator of LIN-12/Notch activity, probably due to defects in endosomal trafficking. Members of the Notch pathway have also been shown to be modifiers of the NBEA homologue in Drosophila, rugose. These new insights in the function of NBEA may help identifying novel pathways affected in autistic patients. In particular, it suggests that impaired functionality of LDCVs, which contain neurotrophins, neuropeptides and monoamines, might contribute to the pathogenesis of autism in at least a subgroup of patients.

The genetics of birth timing: insights into a fundamental component of human development.

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.

Differentiation between wheat chromosomes 4B and 4D

A linkage map based on homoeologous recombination, induced by the absence of the Ph1 locus, between chromosome 4D of Triticum aestivum L. (genomes AABBDD) and chromosome 4B of T. turgidum L. (genomes AABB) was compared with a linkage map of chromosome 4Am of T. monococcum L. and a consensus map of chromosomes 4B and 4D of T. aestivum based on homologous recombination. The 4D/4B homoeologous map was only one-third the length of the homologous maps and all intervals were reduced relative to the 4B-4D consensus map. After the homoeologous map was corrected for this overall reduction in recombination, the distribution of recombination in the short arm was similar in both types of maps. In the long arm, homoeologous recombination declined disproportionally in the distal to proximal direction. This gradient was shown to be largely caused by severe segregation distortion reflecting selection against 4D genetic material. The segregation distortion had a maximum that coincided with the centromere and likely had a polygenic cause. Chromosomes 4D and 4B were colinear and recombination between them occurred in almost all intervals where homologous recombination occurred. These findings suggest that these chromosomes are not differentiated structurally and that the differentiation is not segmental. In the presence of Ph1, metaphase I chromosome pairing between chromosomes composed of homologous and differentiated regions correlated with the lengths of the homologous regions. No compensatory allocation of crossovers into the homologous regions was detected. In this respect, the present results are in dramatic contrast with the crossover allocation into the pseudoautosomal region in the mammalian male meiosis.

Extrahepatic biliary atresia and associated anomalies: etiologic heterogeneity suggested by distinctive patterns of associations.

Fifty-one cases of extrahepatic biliary atresia (EHBA) with associated anomalies were found in a study of EHBA (251 cases). Analysis of segregation patterns of these anomalies in individual patients suggested the existence of 2 major groups: (1) 15 cases (29.4%) with various combinations of anomalies within the laterality sequence, and (2) 30 cases (58.8%) with one or 2 anomalies mostly involving the cardiac, gastrointestinal, and urinary systems. These latter anomalies did not follow any recognizable pattern. The third group of 6 cases all had intestinal malrotation, some with preduodenal portal vein; these cases show some similarity to the laterality sequence group and may represent a more confined phenotypic result of faulty situs determination. This previously unattempted classification of patients with EHBA and associated anomalies might enable a more targeted approach towards identification of causes in this heterogeneous disorder. EHBA within the laterality sequence might prove a suitable candidate for a major gene mutation. Teratogenic, infectious and polygenic multifactorial causes might play a more significant role in EHBA associated with "nonsyndromic" organ system anomalies.