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PubMed1997

Evolving methods in genetic epidemiology. IV. Approaches to non-Mendelian inheritance.

From this overview it can be concluded that the understanding of the biologic properties and the development of analytic tools to identify repeat sequence mutations, genomic imprinting effects, and mitochondrial mutations are only beginning. Development of approaches to identify such phenomena as modifying effects or genetic components of complex traits is a new area of research. Not mentioned here are the ways in which locating a gene with such properties (i.e., linkage analysis) would be affected if such properties were not accounted for, or how to alter such analyses to obtain full information. Again, this is an exciting new area of research that will continue to motivate epidemiologists and geneticists. Hopefully, we have learned a lesson from the earlier conclusions of the studies on myotonic dystrophy: keep an open mind and never assume that the "geneticist should know best about behavior of genes".

Epidemiologic Methods↗

PubMed1997

Integration of classical and molecular approaches of genetic selection: egg production.

Poultry breeding has demonstrated success from the use of a complex mixture of assessment tools. New proposals are regularly sought out and tested for their ability to translate data into information that enhances genetic gain from selection. Details long hidden from view are already being uncovered by molecular genetics, calling for great skill and discipline to discern and harness their real potential. Some aspects of egg production grudgingly may yield to the influence of new associations suggested from molecular work. In particular, diverse environments call for the kind of genetic variation found only under expensive multiple-location testing, longer flock production life calls for better early predictors, and new egg products call for novel measures of egg component value. In the final analysis, selection on a mix of phenotypic and molecular data is an essential step in evaluating its worth for improving a physiologically complex trait like egg production.

Animals↗

PubMed2006

Early responses in the Arabidopsis-Verticillium longisporum pathosystem are dependent on NDR1, JA- and ET-associated signals via cytosolic NPR1 and RFO1.

The responses of Arabidopsis accessions and characterized genotypes were used to explore components in the early defense responses to the soilborne fungus Verticillium longisporum. V. longisporum susceptibility was found to be a complex trait, in which different disease phenotypes, such as stunting, altered flowering time, weight loss, and chlorosis were perceived differently across genotypes. A Bay-0 x Shahdara recombinant inbred line population was used to identify two loci on chromosomes 2 and 3 of Bay-0 origin that caused enhanced chlorosis after V. longisporum challenge. Furthermore, the observation that a mutation in RFO1 in Col-0 resulted in susceptibility whereas the natural rfo1 allele in Ty-0 showed a high degree of resistance to the pathogen supports the hypothesis that several resistance quantitative trait loci reside among Arabidopsis accessions. Analysis of mutants impaired in known pathogen response pathways revealed an enhanced susceptibility in ein2-1, ein4-1, ein6-1, esa1-1, and pad1-1, but not in other jasmonic acid (JA)-, ethylene (ET)-, or camalexin-deficient mutants, suggesting that V. longisporum resistance is regulated via a hitherto unknown JA- and ET-associated pathway. Pretreatments with the ET precursor 1-aminocyclo-propane-1-carboxylic acid (ACC) or methyl jasmonate (MeJA) caused enhanced resistance to V. longisporum. Mutants in the salicylic acid (SA) pathway (eds1-1, NahG, npr1-3, pad4-1, and sid2-1) did not show enhanced susceptibility to V. longisporum. In contrast, the more severe npr1-1 allele displayed enhanced V. longisporum susceptibility and decreased responses to ACC or MeJA pretreatments. This shows that cytosolic NPR1, in addition to SA responses, is required for JA- and ET-mediated V. longisporum resistance. Expression of the SA-dependent PR-1 and PR-2 and the ET-dependent PR-4 were increased 7 days postinoculation with V. longisporum. This indicates increased levels of SA and ET in response to V. longisporum inoculation. The R-gene signaling mutant ndr1-1 was found to be susceptible to V. longisporum, which could be complemented by ACC or MeJA pretreatments, in contrast to the rfo1 T-DNA mutant, which remained susceptible, suggesting that RFO1 (Fusarium oxysporum resistance) and NDR1 (nonrace specific disease resistance 1) activate two distinct signaling pathways for V. longisporum resistance.

Acetates↗

PubMed2004

A variant of porcine thyroxine-binding globulin has reduced affinity for thyroxine and is associated with testis size.

The field of genomics applies the dissection of genetic differences toward an understanding of the biology of complex traits. Quantitative trait loci (QTL) for testis size, plasma FSH in boars, and body composition (backfat) have been identified near the centromere on the X chromosome in a Meishan-White Composite resource population. Since thyroid function affects Sertoli cell development and adult testis size in rodents, and thyroxine-binding globulin (TBG) maps to this region on the porcine X chromosome, TBG was a positional candidate gene for testis size. We discovered a polymorphism in exon 2 of the porcine TBG gene that results in an amino acid change of the consensus histidine to an asparagine. This single nucleotide polymorphism (SNP) resides in the ligand-binding domain of the mature polypeptide, and the Meishan allele is the conserved allele found in human, bovine, sheep, and rodent TBG. Binding studies indicate altered binding characteristics of the allelic variants of TBG with the asparagine (White Composite) isoform having significantly greater affinity for thyroxine than the histidine (Meishan) isoform. Alternate alleles in boars from the resource population are also significantly associated with testis weight. Therefore, this polymorphism in TBG is a candidate for the causative variation affecting testis size in boars.

Amino Acid Sequence↗

PubMed2000

Circulating amylin in human essential hypertension: heritability and early increase in individuals at genetic risk.

BACKGROUND: Human essential hypertension is a complex trait with poorly understood genetic determination. Insulin resistance is frequently associated with this trait. OBJECTIVE: To determine whether a potentially pathogenic feature of the insulin-resistant state, circulating amylin (islet amyloid polypeptide, co-released with insulin from pancreatic islet beta-cells), is already increased in prehypertensive individuals (normotensive persons at genetic risk of hypertension because of family history), whether such individuals already differ in their amylin response to beta-cell stimulation, and whether plasma amylin concentration is heritable. Such features could establish increased circulating amylin as a hereditary 'intermediate phenotype' useful in genetic analyses of hypertension. METHODS: Plasma amylin and insulin were measured in 283 medication-free individuals stratified by blood pressure status (82 hypertensive and 201 normotensive), and genetic risk (family history) of hypertension. Differences in means were tested by ANOVA, variances by F test, and frequency distributions by maximum likelihood analysis. Co-release of amylin and insulin was provoked by intravenous infusion of mixed amino acids. The effect of antihypertensive treatment was evaluated after monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade in hypertension. RESULTS: Plasma amylin was increased in hypertension (P= 0.027), and body mass index was a strong predictor of increased circulating amylin (P = 0.0001). Plasma amylin and plasma renin activity were not correlated (P = 0.395), and effective antihypertensive monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade did not affect either amylin (P = 0.87-0.97) or insulin (P= 0.55-0.59). Among normotensive individuals, those at genetic risk of hypertension (with positive family history) already had increased concentrations of amylin (P< 0.001), despite exhibiting no difference in blood pressure or body mass index compared with the family-history-negative group; however, among normotensive individuals, both family history (P = 0.043) and body mass index (P= 0.0059) were significant predictors of increased concentrations of amylin. By maximum likelihood analysis, plasma amylin was distributed heterogeneously in the normotensive individuals, with two modes best explaining the distribution (chi2 = 77.4, P< 0.001), and family-history-positive individuals completely accounting for the upper mode (chi2 = 4.63, P = 0.031). Family-history-positive normotensive individuals showed greater plasma amylin concentrations both before and during beta-cell stimulation by amino acid infusion (P = 0.014). Black (n = 111) and white (n = 172) individuals did not differ in mean (P = 0.946) or variance (P = 0.172) of plasma amylin concentrations. CONCLUSIONS: These results suggest that plasma amylin concentration is in part determined by heredity. Both basal and stimulated plasma amylin excess may identify a subgroup of individuals bearing an inherited predisposition to hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relationship to insulin resistance.

Adult↗

PubMed2002

Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension.

BACKGROUND: Hypertension is a complex trait with an ill-defined genetic predisposition, in which adrenergic mechanisms seem to be involved even at the early stages. Chromogranin A is a pro-hormone stored and released with catecholamines by exocytosis; its fragment catestatin, formed in vivo, inhibits further catecholamine release as an antagonist at the physiologic trigger for secretion, the neuronal nicotinic cholinergic receptor. METHODS: We measured catestatin by radioimmunoassay in n = 277 subjects stratified by blood pressure (n = 61 hypertensive, n = 216 normotensive), and if normotensive by genetic risk of developing hypertension: family history positive (n = 176) versus negative (n = 40). Maximum likelihood analysis tested for bimodality. Involvement of catestatin in pathophysiology was probed by measurements of catecholamines and leptin, and the hemodynamic responses to environmental (cold) stress. RESULTS: The normotensive offspring of patients with hypertension already had diminished catestatin (P = 0.024), and family history was a better predictor of catestatin than age, ethnicity or gender (P = 0.014). Greater catestatin variance among family history-positive individuals (P = 0.021) suggested heterogeneity in this group, and a bimodal distribution (P < 0.001) identified 4.3% of individuals in a lower mode of catestatin values, all with positive family histories (P = 0.05). Catestatin correlated inversely with body mass index (r = -0.215, r(2) = 0.046, n = 276, P < 0.001) and plasma leptin (r = -0.203, r(2) = 0.041, n = 212, P = 0.003), while body mass index and leptin correlated directly (r = 0.59, r(2) = 0.350, n = 212, P < 0.001). Family history-positive individuals had greater epinephrine excretion (P = 0.037) in addition to diminished catestatin, suggesting an inhibitory effect of catestatin on chromaffin cells in vivo. Low plasma catestatin predicted enhanced pressor response to a sympathoadrenal stressor (cold stress; r = -0.184, r(2) = 0.034, n = 211, P = 0.007), suggesting an adrenergic mechanism whereby diminished catestatin might predispose to later development of hypertension. In white subjects, diminished catestatin also predicted greater systemic vascular resistance responses to cold stress (r = -0.307, r(2) = 0.094, n = 75, P = 0.007), a relationship not found in Blacks (r = 0.122, r(2) = 0.015, n = 94, P = 0.243). CONCLUSIONS: We conclude that catestatin is diminished early in the course of development of hypertension, even in the normotensive offspring of patients with the disease. Low catestatin predicts augmented adrenergic pressor responses, suggesting a mechanism whereby diminished catestatin might increase the risk for later development of hypertension.

Adult↗

PubMed1999

Role of genetic factors in the etiology of juvenile-onset myopia based on a longitudinal study of refractive error.

In an attempt to determine the role of genetic factors in the development of myopia, we examined the relationship of infantile refractive error and parental history to juvenile-onset myopia and analyzed 43 pedigrees affected by juvenile-onset myopia. Refraction data collected at regular intervals from a sample of juvenile subjects participating in a 24-year longitudinal study of refractive error were used. Results showed that children with two myopic parents were 6.42 times as likely to become myopic as children with one or no myopic parents. Furthermore, children who had refractions in the lower half of the distribution at 6 to 12 months of age were 4.33 times as likely to develop myopia as children who had refractions in the upper half of the distribution at 6 to 12 months of age. The pedigree analysis indicated that 63% of individuals considered at risk for developing juvenile-onset myopia actually became myopic, with an equal number of affected males and females. These results suggest that juvenile-onset myopia of moderate amounts may be inherited as a complex trait involving both genetic and environmental factors.

Adolescent↗

PubMed1996

Genetic epidemiology of multiple sclerosis.

Multiple sclerosis appears to be a complex trait determined by genes and environmental factors. This hypothesis is increasingly supported by genetic epidemiological studies of large populations. Well ascertained studies of adoptees and half siblings indicate that familial aggregation is genetic. These results have important implications for the nature of environmental factors influencing susceptibility to multiple sclerosis. These appear to act at a population level and probably exert an influence on risk that matches or exceeds that from any single genetic locus. The identification of susceptibility genes in multiple sclerosis will be difficult.

Canada↗

PubMed2000

Susceptibility to multiple sclerosis: interplay between genes and environment.

Multiple sclerosis is a complex trait of unknown etiology. Epidemiological data have shown that susceptibility to multiple sclerosis is determined by both genetic and environmental factors. It is unknown whether the clinical subcategories of multiple sclerosis are separate diseases with separate etiologies and causes. Recent theories of the pathogenesis of multiple sclerosis and candidate genes are discussed. Other potential nonchromosomal factors involved in multiple sclerosis susceptibility such as mitochondrial DNA and viral factors such as Chlamydia pneumoniae are reviewed.

Environmental Exposure↗

PubMed2002

Treasure hunting in a new era: genotyping of single nucleotide polymorphisms and the search for complex disease genes by association scans.

Genotyping single nucleotide polymorphisms by technologies like those described in this issue are propelling us towards a new era in the study of human genetics. This new era promises improved prospects for mapping genes responsible for complex human diseases and other complex traits. In this article, I sketch empirical results and statistical theory that together form the scientific rationale for anticipating enhanced success in gene mapping in the new era that is now approaching.

Genetic Diseases, Inborn↗

PubMed2004

Angiotensinogen promoter haplotypes are associated with blood pressure in untreated hypertensives.

BACKGROUND: The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for blood pressure (BP) regulation and essential hypertension. OBJECTIVES: To investigate whether AGT haplotype analysis adds significant information compared to single polymorphism analysis with respect to different BP phenotypes in an untreated hypertensive sample. METHODS: Two hundred and twelve untreated hypertensive subjects of Caucasian origin were genotyped for the AGT polymorphisms C-532T, A-20C, C-18T, and G-6A. RESULTS: In single variant analyses, untreated hypertensives, carrying the AGT -532T or -6A alleles had significantly higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as ambulatory BP values compared to respective non-carriers. In haplotype-based analyses, combining all four AGT promoter variants, we demonstrate that AGT haplotypes containing different allele combinations at positions -532 and -6 were significantly associated with different BP values: (1) -532T and -6A with higher, (2) -532C and -6G with lower, (3) -532C and -6A with intermediate BP values. Since the result for the -532C/-20A/-18C/-6G haplotype was due to differences between non-carriers and carriers of this haplotype on both chromosomes, a recessive inheritance model for BP effects could be assumed. CONCLUSIONS: Our results designate the C-532T and G-6A as the best candidates for functional studies on the AGT gene. Haplotype-based analyses should greatly aid in the dissection of the genetic basis of complex traits, such as BP regulation and hypertension.

Adult↗

PubMed2006

A new method for grading the severity of keratoconus: the Keratoconus Severity Score (KSS).

PURPOSE: To define a new method for grading severity of keratoconus, the Keratoconus Severity Score (KSS). METHODS: A rationale for grading keratoconus severity was developed using common clinical markers plus 2 corneal topographic indices, creating a 0 to 5 severity score. An initial test set of 1012 eyes, including normal eyes, eyes with abnormal corneal and topographic findings but not keratoconus, and eyes with keratoconus having a wide range of severity, was used to determine cutpoints for the KSS. Validation set 1, comprising data from 128 eyes, was assigned a KSS and compared with a clinician's ranking of severity termed the "gold standard" to determine if the scale fairly represented how a clinician would grade disease severity. kappa statistics, sensitivity, and specificity were calculated. A program was developed to automate the determination of the score. This was tested against a manual assignment of KSS in 2121 (validation set 2) eyes from the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study, as well as normal eyes and abnormal eyes without keratoconus. Ten percent of eyes underwent repeat manual assignment of KSS to determine the variability of manual assignment of a score. RESULTS: From initial assessments, the KSS used 2 corneal topography indices: average corneal power and root mean square (RMS) error for higher-order Zernike terms derived from the first corneal surface wavefront. Clinical signs including Vogt striae, Fleischer rings, and corneal scarring were also included. Last, a manual interpretation of the map pattern was included. Validation set 1 yielded a kappa statistic of 0.904, with sensitivities ranging from 0.64 to 1.00 and specificities ranging from 0.93 to 0.98. The sensitivity and specificity for determining nonkeratoconus from keratoconus were both 1.00. Validation set 2 showed kappa statistics of 0.94 and 0.95 for right and left eyes, respectively. Test-retest analysis yielded kappa statistics of 0.84 and 0.83 for right and left eyes, respectively. CONCLUSION: A simple and reliable grading system for keratoconus was developed that can be largely automated. Such a grading scheme could be useful in genetic studies for a complex trait such as keratoconus requiring a quantitative measure of disease presence and severity.

Cornea↗

PubMed2005

Progress toward discerning the genetics of cleft lip.

PURPOSE OF REVIEW: Orofacial clefts are common birth defects with a known genetic component to their etiology. Most orofacial clefts are nonsyndromic, isolated defects, which can be separated into two different phenotypes: (1) cleft lip with or without cleft palate and (2) cleft palate only. Both are genetically complex traits, which has limited the ability to identify disease loci or genes. The purpose of this review is to summarize recent progress of human genetic studies in identifying causal genes for isolated or nonsyndromic cleft lip with or without cleft palate. RECENT FINDINGS: The results of multiple genome scans and a subsequent meta-analysis have significantly advanced our knowledge by revealing novel loci. Furthermore, candidate gene approaches have identified important roles for IRF6 and MSX1. To date, causal mutations with a known functional effect have not yet been described. SUMMARY: With the implementation of genome-wide association studies and inexpensive sequencing, future studies will identify disease genes and characterize both gene-environment and gene-gene interactions to provide knowledge for risk counseling and the development of preventive therapies.

B-Cell Lymphoma 3 Protein↗

PubMed2006

Candidate genes for oral-facial clefts in Guatemalan families.

Nonsyndromic cleft lip +/- cleft palate (CL/P) is a complex trait of unknown etiology. Most genetic studies of CL/P define affection status in a way that ignores subtle subclinical manifestations, resulting in a potential loss of statistical power. This study investigated 10 candidate genes in 155 individuals from 25 Guatemalan CL/P families. High-resolution ultrasound images of the orbicularis oris (OO) muscle were obtained. CL/P was present in 28 family members; an additional 10 had subcutaneous OO muscle defects. Family-based association studies were performed for both narrow (CL/P only) and broad (CL/P plus OO muscle defects) definitions of affection status. PVRL1 was significantly associated under both definitions (P = 0.04, narrow; P = 0.02, broad). Association with JAG2 improved from P = 0.09 under the narrow definition to P = 0.04 under the broad definition. Broadening the oral-facial cleft phenotype to include subclinical variants may improve power in genetic studies.

Chromosome Aberrations↗

PubMed2025

Novel Protein-Altering Variants in Cleft Genes Transmitted in Families With NSCL±P.

BACKGROUND: Pathogenic protein-altering variants play a role in the etiology of nonsyndromic cleft lip with or without palate (nsCL±P), one of the most common craniofacial anomalies. However, the genetic basis of many cases remains unclear, complicating risk prediction for affected families. PURPOSE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to identify pathogenic risk variants. STUDY DESIGN, SETTING, SAMPLE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to identify risk variants. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: Genetic variants. MAIN OUTCOME VARIABLES: Nonsyndromic cleft lip with or without palate (nsCL±P). ANALYSES: Genomes were sequenced at a mean ×30 coverage, and variants were prioritized using CADD (≥20), REVEL (≥0.5), and ACMG/AMP clinical significance criteria. RESULTS: We identified pathogenic protein-altering variants in CHD7 (p.Arg1345His), LRP2 (p.Asp3245Asn), RYR1 (p.Arg2163Leu, p.Pro2903Thr), SHH (p.Met114Val), and WNT3 (p.Ser112Pro) highlighting the role of hedgehog signaling pathway (FDR=5.32e-12) in nsCL±P. These variants were inherited from unaffected parents suggesting an incomplete penetrance of the variant effect. Although mouse data showed that knockout of these genes produces cleft phenotypes, in vivo studies will help us better understand how the consequences of these variants differ from benign mutations. The presence of these protein-altering variants in unaffected parents-incomplete penetrance, provides additional evidence supporting the trait complexity. CONCLUSIONS AND RELEVANCE: This study identified rare, pathogenic protein-altering variants in genes involved in key developmental pathways in African families affected by nsCL±P. These findings highlight the critical role of the hedgehog signaling pathway and related networks in the etiology of nsCL±P. These findings underscore the importance of whole-genome sequencing in genetically diverse populations to uncover novel risk variants. These findings enhance our understanding of the genetic etiology of nsCL±P, particularly in under-represented African populations and support the multifactorial inheritance and the involvement of developmental pathways, such as hedgehog signaling in the etiology of clefting.

Humans↗

PubMed1993

Genetic maps.

The same genetic principles are common to all animals, plants and microorganisms. One consequence of the generality of genetic principles is that methods developed in one organism can often be used in other species. Recent advances in mammalian molecular genetics, genome analysis, and gene mapping have been found to be directly applicable to other animals and even plants. This is facilitating the rapid construction of detailed genetic maps in a wide variety of species. Similar advances are being made in the development of manipulation techniques, which allow the genomic deletion and addition of specific genes as well as more subtle alterations. Armed with detailed maps and precise manipulation techniques it is possible to associate genes with phenotypes, test the function of genes and to unravel complex traits that depend on the interaction of different genes.

Animals↗

PubMed2005

The genetics of human drug response.

The genetics of variable drug response appears to be a more tractable complex trait than common disease predisposition. This has implications for prioritizing research and for experimental design, and in particular argues for extensive use of candidate gene based approaches in pharmacogenetic association studies. Eventually, when whole genome scanning becomes feasible, it may be appropriate to consider weighting schemes that assign higher prior probabilities of variants in genes related to the mode of action of metabolism of medicines.

Genes↗

PubMed2005

Prospects and pitfalls in whole genome association studies.

Recent large-scale studies of common genetic variation throughout the human genome are making it feasible to conduct whole genome studies of genotype-phenotype associations. Such studies have the potential to uncover novel contributors to common complex traits and thus lead to insights into the aetiology of multifactorial phenotypes. Despite this promise, it is important to recognize that the availability of genetic markers and the ability to assay them at realistic cost does not guarantee success of this approach. There are a number of practical issues that require close attention, some forms of allelic architecture are not readily amenable to the association approach with even the most rigorous design, and doubtless new hurdles will emerge as the studies begin. Here we discuss the promise and current challenges of the whole genome approach, and raise some issues to consider in interpreting the results of the first whole genome studies.

Genetic Markers↗