Genomics and medicine: an anticipation. From Boolean Mendelian genetics to multifactorial molecular medicine

The major impact of the completion of the human genome sequence will be the understanding of diseases, with deduced therapy. In the field of genetic disorders, we will complete the catalogue of monogenic diseases, also called Mendelian diseases because they obey the Boolean logic of Mendel's laws. The major challenge now is to decipher the polygenic and multifactorial etiology of common diseases, such as cancer, cardio-vascular, nutritional, allergic, auto-immune and degenerative diseases. In fact, every gene, when mutated, is a potential disease gene, and we end up with the new concept of 'reverse medicine'; i.e., deriving new diseases or pathogenic pathways from the knowledge of the structure and function of every gene. By going from sequence to function (functional genomics and proteomics) we will gain insight into basic mechanisms of major functions such as cell proliferation, differentiation and development, which are perturbed in many pathological processes. By learning the meaning of some non-coding and of regulatory sequences our understanding will gain in complexity, generating a molecular and supramolecular integrated physiology, helping to build a molecular patho-physiology of the different syndromes. Besides those cognitive advances, there are also other issues at stake, such as: progress in diagnostic and prediction (predictive medicine); progress in therapy (pharmacogenomics and gene-based therapy); ethical issues; impact on business.     

Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder

Resorption of amino acids in kidney and intestine is mediated by transporters, which prefer groups of amino acids with similar physico-chemical properties. It is generally assumed that most neutral amino acids are transported across the apical membrane of epithelial cells by system B(0). Here we have characterized a novel member of the Na(+)-dependent neurotransmitter transporter family (B(0)AT1) isolated from mouse kidney, which shows all properties of system B(0). Flux experiments showed that the transporter is Na(+)-dependent, electrogenic, and actively transports most neutral amino acids but not anionic or cationic amino acids. Superfusion of mB(0)AT1-expressing oocytes with neutral amino acids generated inward currents, which were proportional to the fluxes observed with labeled amino acids. In situ hybridization showed strong expression in intestinal microvilli and in the proximal tubule of the kidney. Expression of mouse B(0)AT1 was restricted to kidney, intestine, and skin. It is generally assumed that mutations of the system B(0) transporter underlie autosomal recessive Hartnup disorder. In support of this notion mB(0)AT1 is located on mouse chromosome 13 in a region syntenic to human chromosome 5p15, the locus of Hartnup disorder. Thus, the human homologue of this transporter is an excellent functional and positional candidate for Hartnup disorder.     

Models of multifactorial inheritance: IV, asymmetric transmission for a scalar phenotype

The influence of asymmetric transmission is more finely studied in this paper. We focus on cases of (i) equal parental transmission not necessarily midparental; (ii) maternal and paternal distinguished transmission including the case of strict uniparental transmission; (iii) different levels of transmission depending on the offspring sex; and others. The explicit equilibrium covariance structure is worked out and a number of qualitative properties of the equilibrium variances are delineated as functions of the model parameters.     

The genotype–phenotype distinction: from Mendelian genetics to 21st century biology

Genetica - The Genotype-Phenotype (G-P) distinction was proposed in the context of Mendelian genetics, in the wake of late nineteenth century studies about heredity. In this paper, we provide a...     

Preeclampsia: multiple approaches for a multifactorial disease

Preeclampsia is a pregnancy-specific disorder characterized by hypertension and excess protein excretion in the urine. It is an important cause of maternal and fetal morbidity and mortality worldwide. The disease is almost exclusive to humans and delivery of the pregnancy continues to be the only effective treatment. The disorder is probably multifactorial, although most cases of preeclampsia are characterized by abnormal maternal uterine vascular remodeling by fetally derived placental trophoblast cells. Numerous in vitro and animal models have been used to study aspects of preeclampsia, the most common being models of placental oxygen dysregulation, abnormal trophoblast invasion, inappropriate maternal vascular damage and anomalous maternal-fetal immune interactions. Investigations into the pathophysiology and treatment of preeclampsia continue to move the field forward, albeit at a frustratingly slow pace. There remains a pressing need for novel approaches, new disease models and innovative investigators to effectively tackle this complex and devastating disorder.     

The HLA system and the analysis of multifactorial genetic disease

The human leukocyte antigen (HLA) system comprises closely linked genes controlling highly polymorphic proteins involved in the presentation of peptides to the T-cell receptor. Specific alleles at HLA loci are associated with diseases, often those suspected to be of autoimmune aetiology. Many of these associations result from linkage disequilibrium between the HLA gene studied and other HLA genes or non-HLA gebes close by. Owing to its high level of polymorphism and its candidate role in many diseases, HLA was the first system used in many techniques of genetic mapping, such as affected-sib-pair analysis and association (linkage disequilibrium) studies. Much remains unknown about the reasons why diseases are associated with HLA. Experience gained from HLA has, however, shown how other loci involved in complex traits can be identified by studying families with multiple affected cases or sib pairs, followed by linkage-disequilibrium mapping and then analysis of candidate genes.     

The Genetic Basis of Mendelian Phenotypes: Discoveries,Challenges, and Opportunities

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.     

From genome to aetiology in a multifactorial disease, type 1 diabetes

The common autoimmune disease type 1 diabetes provides a paradigm for the genetic analysis of multifactorial disease. Disease occurrence is attributable to the interaction with the environment of alleles at many loci interspersed throughout the genome. Their mapping and identification is difficult because the disease-associated alleles occur almost as commonly in patients as in healthy individuals; even the highest-risk genotypes bestow only modest risks of disease. The identification of common quantitative trait loci (QTL) in autoimmune disease and in other common disorders, therefore, requires a very close marriage of genetics and biology. Two QTLs have been identified in human type 1 diabetes: the major histocompatibility complex HLA class II loci and a promoter polymorphism of the insulin gene. The evidence for their primary roles in disease aetiology demonstrates the necessity of combined studies of genetics and biology. Their functions and interaction underpin an emerging picture of the basic causes of the disease and direct analyses towards other candidate genes and pathways. The genetic tools used for QTL identification include transgenesis and gene knockouts, whole genome scanning for linkage, mouse congenic strains, linkage disequilibrium mapping, and the establishment of ancestral haplotypes among disease-associated chromosomes.     

Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

Epidemiological research has revealed a galaxy of biomarkers, such as genes, molecules or traits, which are associated with increased risk of atherosclerotic cardiovascular diseases(ASCVD). However, the etiological basis remains poorly characterized.Mendelian randomization(MR) involves the use of observational genetic data to ascertain the roles of disease-associated risk factors and, in particular, differentiate those reflecting the presence or severity of a disease from those contributing causally to a disease. Over the past decade, MR has evolved into a fruitful approach to clarifying the causal relation of a biomarker with ASCVD and to verifying potential therapeutic targets for ASCVD. In this review, we selected high-quality MR studies on ASCVD, examined the causal relationship of a series of biomarkers with ASCVD, and elucidated the role of MR in validating biomarkers as a therapeutic target by comparing the results from MR studies and randomized clinical trials(RCTs) for the treatment of ASCVD. The good agreement between the results derived by MR and RCTs suggests that MR could be performed as a screening process before novel drug development. However, when designing and interpreting a MR study, the assumptions and limitations inherent in this approach should be taken into account. Novel methodological developments, such as sensitivity analysis, will help to strengthen the validity of MR studies.     

Models of multifactorial inheritance: II, the covariance structure for a scalar phenotype under selective assortative mating and sex-dependent symmetric parental-transmission

This study concentrates on a scalar trait for a two-sex population entailing symmetric sex-dependent parent-offspring transmission, a nonlinear (selective) assortative mating pattern, and random perturbation factors. A number of qualitative and comparative properties of the equilibrium covariance structure are set forth. In particular, it is shown that the phenotype variance generally increases under attenuated assortative mating tendencies and for an increased level of parent-offspring transmission. Moreover, with more contrasting sex-dependent transmission the sibling covariances diverge from the parent-offspring covariance. Also, shared residual-environmental covariance enhances the sibling covariances. The absolute product moment of the deviation of a child phenotype from the separate parental phenotypes exhibits a minimum for a mixed assortative random mating scheme rather than under extreme assortative mating or pure random mating. We establish that the equilibrium variance of a married individual is reduced compared to the variance of the population at large. Interpretations and implications are discussed.     

Glycogen storage disease type 1b: genetic disorder involving the transport system of intracellular membrane

Glycogen storage diseases (GSD) type 1b is the first example of a genetic disorder involving the transport system of an intracellular membrane. It was revealed that the primary defect in GSD type 1b was a deficiency in the microsomal glucose-6-phosphate (G6P) translocase, based on the findings that the glucose-6-phosphatase activity was highly latent in the fresh liver homogenates. Further evidence of this defect in GSD type 1b has been provided by a membrane filter method which measures the uptake of 14C-G6P by microsomes. The clinical symptoms and enzymatic studies in our patients suggest that there is genetic heterogeneity in GSD 1b and the clinical severity depends on the level of residual activities of G6P translocase.     

Molecular mechanisms of neurodegeneration in Parkinson's disease: clues from Mendelian syndromes

The recent identification and characterization of gene products responsible for familial forms of Parkinson disease (PD) have provided significant insights into the pathogenesis of PD. Collectively, these studies point towards ubiquitin-proteasome system (UPS) dysfunction as an underlying mechanism responsible for dopaminergic cell death in PD. Emerging evidence further indicates a complex interplay between UPS derangements and other PD pathogenetic factors, all interwoven in an integrated network leading to dopaminergic cell death in PD. Taken together, these findings suggest that neuronal degeneration in PD is a result of a cascade of events, rather than a primary pathogenic event. Here, we review the clues uncovered from various Mendelian-inherited forms of PD that have helped shaped our understanding of the molecular mechanisms underlying PD pathogenesis.     

Lafora disease: from genotype to phenotype

The progressive myoclonic epilepsy of Lafora or Lafora disease (LD) is a neurodegenerative disorder characterized by recurrent seizures and cognitive deficits. With typical onset in the late childhood or early adolescence, the patients show progressive worsening of the disease symptoms, leading to death in about 10 years. It is an autosomal recessive disorder caused by the loss-of-function mutations in the EPM2A gene, coding for a protein phosphatase (laforin) or the NHLRC1 gene coding for an E3 ubiquitin ligase (malin). LD is characterized by the presence of abnormally branched water insoluble glycogen inclusions known as Lafora bodies in the neurons and other tissues, suggesting a role for laforin and malin in glycogen metabolic pathways. Mouse models of LD, developed by targeted disruption of the Epm2a or Nhlrc1 gene, recapitulated most of the symptoms and pathological features as seen in humans, and have offered insight into the pathomechanisms. Besides the formation of Lafora bodies in the neurons in the presymptomatic stage, the animal models have also demonstrated perturbations in the proteolytic pathways, such as ubiquitin-proteasome system and autophagy, and inflammatory response. This review attempts to provide a comprehensive coverage on the genetic defects leading to the LD in humans, on the functional properties of the laforin and malin proteins, and on how defects in any one of these two proteins result in a clinically similar phenotype. We also discuss the disease pathologies as revealed by the studies on the animal models and, finally, on the progress with therapeutic attempts albeit in the animal models.     

The transmission of schizophrenia under a multifactorial threshold model.

Family studies of schizophrenia have reported elevated rates of both definite and definite-plus-probable schizophrenia among the relatives of definite schizophrenics. These elevated rates imply a strong association between the two forms of diagnosis and suggest some form of familial transmission. Here we have used recently developed maximum likelihood methods to investigate this association and characterize the nature of the familial transmission. Results indicated that although the two forms of diagnosis were strongly related, they could not be considered alternative manifestations of a single liability distribution. Heritability estimates for either form of diagnosis were comparable (h2 = .668 +/- .052 and c2 = .191 +/- .038 for definite while h2 = .628 +/- .073 and c2 = .236 +/- .106 for definite-plus-probable), although cultural transmission (i.e., c2) was statistically significant only for definite-plus-probable. For either form of diagnosis, residual twin resemblance was statistically significant and could not be explained in terms of the effects of genetic dominance. These results are comparable to those of an earlier analysis based upon a similar data set. Finally, the statistical correction used to adjust for between-study heterogeneity in morbidity risk figures did not noticeably alter the parameter estimates.     

The multifactorial/threshold concept -- uses and misuses.

The common congenital malformations have familial distributions that cannot be accounted for by simple Mendelian models, but can be explained in terms of a continuous variable, "liability," with a threshold value beyond which individuals will be affected. Both genetic and environmental factors determine liability, making the system multifactorial. Cleft palate is a useful experimental model, illustrating a number of factors that contribute to palate closure, the nature of a developmental threshold, and how genes and teratogens can alter the components of liability to increase the probability of cleft palate. The nature of the genetic component to liability in human malformations in not clear, and various possibilities, ranging from polygenic in the strict sense to a major gene with reduced penetrance are compatible with the data -- but the important feature is the threshold. Much of the confusion over the concept results from inconsistent use of terminology. The term "multifactorial" should be used for "determined by a combination of genetic and environmental factors," without reference to the nature of the genetic factor(s). "Polygenic" should be reserved for "a large number of genes, each with a small effect, acting additively." When several genes, with more major effects are involved, "multilocal" can be used. When it is not clear which of these is applicable the term "plurilocal" is suggested, in the sense of "genetic variation more complex than a simple Mendelian difference." Since teratological data often represent threshold characters the concept also has important implications for the interpretation of data on dose-response curves, synergisms, and strain differences in response to teratogens.