Origins of human genetics. A personal perspective.

Genetics evolved as a field of science after 1900 with new theories being derived from experiments obtained in fruit flies, bacteria, and viruses. This personal account suggests that the origins of human genetics can best be traced to the years 1949 to 1959. Several genetic scientific advances in genetics in 1949 yielded results directly relating to humans for the first time, except for a few earlier observations. In 1949 the first textbook of human genetics was published, the American Journal of Human Genetics was founded, and in the previous year the American Society of Human Genetics. In 1940 in Britain a textbook entitled Introduction to Medical Genetics served as a foundation for introducing genetic aspects into medicine. The introduction of new methods for analyzing chromosomes and new biochemical assays using cultured cells in 1959 and subsequent years revealed that many human diseases, including cancer, have genetic causes. It became possible to arrive at a precise cause-related genetic diagnosis. As a result the risk of occurrence or re-occurrence of a disease within a family could be assessed correctly. Genetic counseling as a new concept became a basis for improved patient care. Taken together the advances in medically orientated genetic research and patient care since 1949 have resulted in human genetics being both, a basic medical and a basic biological science. Prior to 1949 genetics was not generally viewed in a medical context. Although monogenic human diseases were recognized in 1902, their occurrence and distribution were considered mainly at the population level.

Cushing syndrome: Old and new genes.

Cushing syndrome (CS) describes the signs and symptoms caused by exogenous or endogenous hypercortisolemia. Endogenous CS is caused by either ACTH-dependent sources (pituitary or ectopic) or ACTH-independent (adrenal) hypercortisolemia. Several genes are currently known to contribute to the pathogenesis of CS. Germline gene defects, such as MEN1, AIP, PRKAR1A and others, often present in patients with pituitary or adrenal involvement as part of a genetic syndrome. Somatic defects in genes, such as USP8, TP53, and others, are also involved in the development of pituitary or adrenal tumors in a large percentage of patients with CS, and give insight in pathways involved in pituitary or adrenal tumorigenesis.

An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma.

Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.

Old and new genes in primary aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension affecting 5%-10% of patients with arterial hypertension. In PA, high blood pressure is associated with high aldosterone and low renin levels, and often hypokalemia. In a majority of cases, autonomous aldosterone production by the adrenal gland is caused by an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). During the last ten years, a better knowledge of the pathophysiology of PA came from the discovery of somatic and germline mutations in different genes in both sporadic and familial forms of the disease. Those genes code for ion channels and pumps, as well as proteins involved in adrenal cortex development and function. Targeted next generation sequencing following immunohistochemistry guided detection of aldosterone synthase expression allows detection of somatic mutations in up to 90% of APA, while whole exome sequencing has discovered the genetic causes of four different familial forms of PA. The identification, in BAH, of somatic mutations in aldosterone producing cell clusters open new perspectives in our understanding of the bilateral form of the disease and the development of new therapeutic approaches.

Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.

OBJECTIVE: Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. METHODS: Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. RESULTS: A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. CONCLUSION: Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFß (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.

Werner syndrome (WRN) gene variants and their association with altered function and age-associated diseases.

Werner syndrome (WS) is a heritable autosomal recessive human disorder characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients, WRN, is encoded by a member of the human RECQ gene family that contains both a DNA exonuclease and a helicase domain. WRN has been shown to participate in several DNA metabolic pathways including DNA replication, recombination and repair, as well as telomere maintenance and transcription modulation. Here we review base pair-level genetic variation that has been documented in WRN, with an emphasis on non-synonymous coding single nucleotide polymorphisms (SNPs) and their associations with anthropomorphic features, longevity and disease risk. These associations have been challenging to identify, as many reported WRN SNP associations appear to be further conditioned upon ethnic, age, gender or other environmental co-variables. The WRN variant phenotypic associations identified to date are intriguing, and several are of clear clinical import. Consequently, it will be important to extend these initial associations and to identify the mechanisms and conditions under which specific WRN variants may compromise WRN function to drive cellular and organismal phenotypes as well as disease risk.

Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies.

Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation.

From integrative genomics to therapeutic targets.

Combinatorial approaches that integrate conventional pathology with genomic profiling and functional genomics have begun to enhance our understanding of the genetic basis of breast cancer. These methods have identified key genotypic-phenotypic correlations in different breast cancer subtypes that have led to the discovery of genetic dependencies that drive their behavior. Moreover, this knowledge has been applied to define novel tailored therapies for these groups of patients with cancer. With the current emphasis on characterizing the mutational repertoire of breast cancers by next-generation sequencing, the question remains as to what constitutes a driver event. By focusing efforts on homogenous subgroups of breast cancer and integrating orthogonal data-types combined with functional approaches, we can begin to unravel the heterogeneity and identify aberrations that can be therapeutically targeted.

Association between single nucleotide polymorphisms of the transforming growth factor-ß1 gene and overall survival in unresectable locally advanced non-small-cell lung cancer patients treated with radio(chemo)therapy in a Chinese population.

The outcome is variable for unresectable locally advanced non-small-cell lung cancer (ULANSCLC) patients treated with radio(chemo)therapy. The aim of this study is to investigate whether single-nucleotide polymorphisms (SNPs) in the transforming growth factor-beta1 (TGF-ß1) gene are associated with overall survival (OS) in ULANSCLC patients treated with definitive radio(chemo)therapy. A total of 109 patients who had available blood samples and complete clinical and follow-up information were enrolled. DNA from blood was genotyped for two SNPs: TGF-ß1 C-509T and T+869C. Kaplan-Meier survival analysis, log-rank test, and Cox's proportional hazard model were used to evaluate associations between genotypes and OS. Log-rank test showed that TGF-ß1 C-509T significantly correlated with OS (pooled P = 0.017). Both univariate and multivariate analyses showed that TGF-ß1 C-509T CC genotype was significantly associated with better OS than CT or TT genotypes. These results indicate that TGF-ß1 C-509T CC genotype is significantly associated with better OS in ULANSCLC patients treated with radio(chemo)therapy as a potential independent survival predictor.

Genetic architecture of declarative memory: implications for complex illnesses.

Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.

Genetic basis for susceptibility to lung cancer: Recent progress and future directions.

Lung cancer is the leading cause of cancer death worldwide, and cigarette smoking is the major environmental factor for its development. To elucidate the genetic differences in the susceptibility to lung cancer among individuals, genetic factors involved in tobacco-induced lung cancers have been extensively investigated and a number of genetic polymorphisms have been identified to date as candidates. Most of the polymorphisms identified are of genes encoding proteins associated with the activity to metabolize tobacco smoke carcinogens and to suppress mutations induced by those carcinogens, and functional significances have been elucidated for some of these polymorphisms. However, the significance of these polymorphisms in the contribution to lung cancer development still remains unclear. Recently, several novel lung cancer susceptibility genes, including those on chromosomes 5p15.33, 6p21, and 15q24-25.1, have been identified by large-scale genome-wide association (GWA) studies. The 15q25 region contains three nicotine acetylcholine receptor subunit genes, and their polymorphisms have been also reported as being associated with nicotine dependence. The 5p15.33 region is associated with risks specifically for lung adenocarcinoma, the commonest histological type and weakly associated with smoking. This locus has been shown to be associated with risks for a wide variety of cancers, including lung adenocarcinoma. Associations of the 6q21 region have not been consistently replicated among studies. The 6q23-25 and 13q31.3 regions were also identified by recent GWA studies as being associated with risk for lung cancer, particularly in never-smokers. However, contributions of genetic differences on these five loci to the susceptibility to overall lung cancer seem to be small. There are several molecular pathways for the development of lung adenocarcinomas, and environmental factors for their development are still unclear, especially those in never-smokers. In addition, geographic differences as well as gender differences in lung cancer risk have been indicated. Furthermore, various genes identified by candidate gene association studies have not been reevaluated for their significance together with genes identified by GWA studies in the same population. Therefore, further studies will be necessary to assess the individual susceptibility to lung cancer based on the combination of polymorphisms in multiple genes, and to establish a novel way of evaluating the individual risk for lung cancer for its prevention.

Mitochondrial translation initiation factor 3 polymorphism and Parkinson's disease.

Mitochondrial dysfunction has been proposed to play a role in the pathogenesis of Parkinson's disease (PD). Supportive of this hypothesis, several genetic variants that regulate mitochondrial function and homeostasis have been described to alter PD susceptibility. A recent report demonstrated association of a single nucleotide polymorphism in the mitochondrial translation initiation factor 3 (MTIF3) gene with PD risk. The protein encoded by this nuclear gene is essential for initiation complex formation on the mitochondrial 55S ribosome and regulates translation of proteins within the mitochondria. Changes in the function or expression of the MTIF3 protein may result in altered mitochondrial function, ATP production or formation of reactive oxygen species thereby affecting susceptibility to PD. We examined the association of rs7669 with sporadic PD in three Caucasian case control series (n=2434). A significant association was observed in the largest series (Norwegian; n=1650) when comparing CC vs. CT/TT genotypes, with the Irish and US series having a similar but non-significant trend. The combined series also revealed an association with risk of PD (P=0.01), supporting the possible involvement of this gene in PD etiology.

Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common variants predisposing to atrial fibrillation, Crohn disease, multiple sclerosis, rheumatoid arthritis, or type 2 diabetes were successfully genotyped in 9483 samples accrued over 4 mo into BioVU, the Vanderbilt University Medical Center DNA biobank. Previously reported odds ratios (OR(PR)) ranged from 1.14 to 2.36. For each phenotype, natural language processing techniques and billing-code queries were used to identify cases (n = 70-698) and controls (n = 808-3818) from deidentified health records. Each of the 21 tests of association yielded point estimates in the expected direction. Previous genotype-phenotype associations were replicated (p < 0.05) in 8/14 cases when the OR(PR) was > 1.25, and in 0/7 with lower OR(PR). Statistically significant associations were detected in all analyses that were adequately powered. In each of the five diseases studied, at least one previously reported association was replicated. These data demonstrate that phenotypes representing clinical diagnoses can be extracted from EMR systems, and they support the use of DNA resources coupled to EMR systems as tools for rapid generation of large data sets required for replication of associations found in research cohorts and for discovery in genome science.

Recent progress in the genetics of Wegener's granulomatosis and Churg-Strauss syndrome.

PURPOSE OF REVIEW: Recently, numerous studies have been performed to elucidate the genetic background of Wegener's granulomatosis and Churg-Strauss syndrome (CSS). Many of these investigations suffer from low statistical power, inconsistent case classification and other error-prone study designs. The majority of these findings has to be considered preliminary, if not spurious. We summarize the most important and robust findings. RECENT FINDINGS: HLA-DPB1, the association of which with Wegener's granulomatosis has been discovered some years ago, is still the strongest and best replicated risk locus for this condition. Yet, no association is demonstrable for CSS, in which another HLA locus, HLA-DR, seems to be more important. Vice versa, a strong association with IL10 promotor polymorphisms was detected in CSS but not in a large Wegener's granulomatosis panel. Numerous other associations, including CTLA4, CD226 and copy number polymorphisms of FCGR3B still need further investigation, before reliable conclusions can be drawn. SUMMARY: In order to be able to evaluate critically the genetic background of Wegener's granulomatosis and CSS future projects should take into account several aspects of study design. These preconditions include sufficient numbers of cases (i.e. statistical power) and a clear-cut classification of these cases, thus allowing differentiated analyses of certain disease subgroups.

Future nutrigenetics: in search of the missing genetic variation.

Despite considerable effort, genetic analysis of complex disorders and traits, including those related to nutrition, has revealed only a very small part of the expected genetic variation. Missing variation may occur as conditional variation depending on the presence of defined lifestyle factors, as epigenetic variation or as low-moderate effect size variation not detected by mutation screening and genome-wide association studies. Experience with genetic analysis of patients with neural tube defects provides evidence of the existence of the latter type of variation and demonstrates that candidate gene analysis is an efficient approach to discover part of this missing variation. By reviewing the genes with rare and common variation associated with obesity or related parameters, guidelines are proposed for the proper selection of candidate genes. This selection fits into an analytic strategy to deal with the complex and massive data sets expected to arise from the application of routine whole genome sequencing.