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Results for “Mendelian Randomization Analysis”

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PubMed2003

Population structure of São Miguel Island, Azores: a surname study.

The knowledge of a population structure may constitute a powerful tool for mapping genes underlying susceptibility to Mendelian and complex diseases. To obtain a better understanding of the population structure of São Miguel Island (Azorean Archipelago, Portugal), we carried out a surname survey using the surnames listed in the most recent telephone book (2001). We identified 1315 different surnames in a total of 27,621 subscribers. The frequency of the different surnames was used to calculate the following parameters: isonymy (I), random component of inbreeding (FST), genetic diversity according to Fisher (alpha), migration rate according to Karlin-McGregor (v) and Nei's genetic distance. Eleven localities were selected, according to population size and geographic distribution, for analysis using the above parameters. Our results show that 51% of Salga's population and 52% of Sete Cidades's population are represented by six and eight surnames, respectively. These figures demonstrate the effective isolation of these two small places, which are located at opposite ends of São Miguel Island. Salga, Achada, and Sete Cidades present the lowest values of Fisher's alpha, indicating less genetic diversity. In contrast, the capital, Ponta Delgada, presents the highest value of alpha (78.13), indicating more genetic diversity. Our data indicate that the clustering of the localities corresponds to the geographic features of the island, where localities close together tend to share similar surnames. In conclusion, the population of São Miguel is relatively homogeneous and may constitute an ideal model for genetic mapping studies.

Azores↗

PubMed2001

Difficulties in parentage analysis: the probability that an offspring and parent have the same heterozygous genotype.

Parentage studies often estimate the number of parents contributing to half-sib progeny arrays by counting the number of alleles attributed to unshared parents. This approach is compromised when an offspring has the same heterozygous genotype as the shared parent, for then the contribution of the unshared parent cannot be unambiguously deduced. To determine how often such cases occur, formulae for co-dominant markers with n alleles are derived here for Ph, the probability that a given heterozygous parent has an offspring with the same heterozygous genotype, and Pa, the probability that a randomly chosen offspring has the same heterozygous genotype as the shared parent. These formulae have been derived assuming Mendelian segregation with either (1) an arbitrary mating system, (2) random mating or (3) mixed mating. The maximum value of Pa under random mating is 0.25 and occurs with any two alleles each at a frequency of 0.5. The behaviour with partial selfing (where reproduction is by selfing with probability s, and random mating otherwise) is more complex. For n < or = 3 alleles, the maximum value of Pa occurs with any two alleles each at a frequency of 0.5 if s < 0.25, and with three equally frequent alleles otherwise. Numerically, the maximum value of Pa for n > or = 4 alleles occurs with n* < or = n alleles at equal frequencies, where the maximizing number of alleles n* is an increasing function of the selfing rate. Analytically, the maximum occurs with all n alleles present and equally frequent if s > or = 2/3. In addition, the potential applicability of these formulae for evolutionary studies is briefly discussed.

Alleles↗

PubMed2002

A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas.

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2-3 for first-degree relatives and 1.6 for third-degree relatives. The risk of RCC is significantly higher for members of the extended family of an affected individual, as well as the nuclear family. Our results indicate that germline mutations are significantly involved in what has been defined as sporadic RCC.

Adult↗

PubMed2005

Allopolyploidy in wheat induces rapid and heritable alterations in DNA methylation patterns of cellular genes and mobile elements.

Whereas accumulating recent evidences indicate that allopolyploid formation in plants is accompanied by rapid and non-Mendelian genomic changes, some other works showed genomic stasis in both nascent and natural allopolyploids. To further study the issue, we performed global DNA fingerprinting of a newly synthesized allohexaploid wheat and its natural counterpart, the common wheat, by AFLP analysis. It was found that ca. 20% bands showed deviation from parental additivity in both synthetic and the natural common wheat. Sequence analysis indicates that a majority of the changed bands represent known-function genes and transposable elements. DNA gel blot analysis showed that the main type of changes in the amphiploid is epigenetic in nature, i.e., alteration in DNA methylation patterns. Two types of alterations in methylation, random and non-random, were detected, and both types were stably inherited. Possible causes and implications of the epigenetic changes in allopolyploid genome evolution and speciation are discussed.

DNA Methylation↗

PubMed1983

Evaluation of random cDNA clones as probes for human restriction fragment polymorphisms.

The purpose of this study was to evaluate the usefulness of randomly isolated human cDNA clones as probes for human restriction fragment polymorphisms. Clones were chosen from two human cDNA libraries and tested by hybridization against Southern blots of genomic DNA prepared from nine individuals. Three types of hybridization patterns were seen with the individual clones tested, those representative of single copy genes, others representative of gene families, and one characteristic of a mitochondrial gene. Only two of these cDNA clones revealed any polymorphisms among the individuals tested: pDK-08 and RW12, both representative of gene families. Both revealed independent polymorphisms with several of the restriction enzymes tested, and inheritance of these polymorphisms as Mendelian alleles was verified by human pedigree analysis. The results are discussed with regard to the usefulness of such cDNA clones in revealing polymorphisms in human genetic analysis.

Cloning, Molecular↗

PubMed1998

Major locus influencing plasma APO-A1 levels also controls plasma HDL3-C concentrations.

Elevated plasma levels of apolipoprotein A1 (APO-A1) and high-density lipoprotein cholesterol (HDL-C) are important protective factors for atherosclerosis and coronary heart disease. Using the data on plasma concentrations of APO-A1, and HDL-C particles HDL2-C and HDL3-C in 970 Israeli individuals belonging to 228 pedigrees, we tested the hypothesis that a major locus influencing interindividual variation in APO-A1 levels also controls interindividual variation in HDL3-C and HDL2-C levels. Univariate and bivariate complex segregation analyses, as implemented in two statistical packages (MAN-3 and PAP-4.0) were applied to test the hypothesis. The results of the analysis clearly indicated the possibility of major gene involvement in the determination of plasma concentration variation of each of the 3 study variables. The results provide strong evidence in support of our hypothesis that HDL3-C genetic variation fully depends on the APO-A1 major locus. In particular, environmental and sporadic models were strongly rejected (P < 0.001) in bivariate analysis. The hypothesis of no pleiotropic effect of the putative APO-A1 locus on HDL3-C transmission was also unequivocally rejected (P < 0.001), while the bivariate Mendelian model was accepted (P > 0.05). The results of bivariate analysis of APO-A1 effect on HDL2-C were not clear. They indicated the possibility of the existence of slight genetic covariation between the two variables, and as yet we were unable to decipher the mode of covariation with the applied models.

Apolipoprotein A-I↗

PubMed2002

Allozyme analysis of cryptic species in the Asplenium niduscomplex from West Java, Indonesia.

In various fern species, a large amount of rbcL sequence variation has been reported, and it is possible that these species contain several reproductively isolated cryptic species. In our previous study on Asplenium nidus L., it was suggested that the plants growing in Mt. Halimun National Park, West Java, Indonesia, consist of several cryptic species based on the results of crossing experiments among rbcL sequence types. In this study, we examined allozyme polymorphisms of five rbcL sequence types found in West Java in order to test the hypothesis that the assemblages of A. nidus delimited based on the rbcL sequences are separate Mendelian populations and gene flow is disrupted by reproductive isolation from one another. The calculated fixation indices suggested that the individuals in each rbcL type are randomly crossing at least in the investigated localities. Nevertheless, these rbcL-based assemblages were genetically differentiated in allozymes that are encoded in their nuclear genomes, and it is also suggested that gene flow is disrupted even between sympatrically distributed pairs of rbcL sequence types. Therefore, our findings support the view that the five rbcL sequence types in West Java are potential cryptic species.

Journal Article↗

PubMed2004

Testing for association with a case-parents design in the presence of genotyping errors.

Genotyping errors can create a problem for the analysis of case-parents data because some families will exhibit genotypes that are inconsistent with Mendelian inheritance. The problem with correcting Mendelian inconsistent genotype errors by regenotyping or removing families in which they occur is that the remaining unidentified genotype errors can produce excess type I (false positive) error for some family-based tests for association. We address this problem by developing a likelihood ratio test (LRT) for association in a case-parents design that incorporates nuisance parameters for a general genotype error model. We extend the likelihood approach for a single SNP to include short haplotypes consisting of 2 or 3 SNPs. The extension to haplotypes is based on assumptions of random mating, multiplicative penetrances, and at most a single genotype error per family. For a single SNP, we found, using Monte Carlo simulation, that type I error rate can be controlled for a number of genotype error models at different error rates. Simulation results suggest the same is true for 2 and 3 SNPs. In all cases, power declined with increasing genotyping error rates. In the absence of genotyping errors, power was similar whether nuisance parameters for genotype error were included in the LRT or not. The LRT developed here does not require prior specification of a particular model for genotype errors and it can be readily computed using the EM algorithm. Consequently, this test may be generally useful as a test of association with case-parents data in which Mendelian inconsistent families are observed.

Adult↗

PubMed1993

The analysis of paternity and maternity in the marine hydrozoan Hydractinia symbiolongicarpus using randomly amplified polymorphic DNA (RAPD) markers.

For organisms in which direct observation of mating and subsequent dispersal of offspring and relatives is impossible, patterns of reproductive success and genealogical relationship can only be established using genetic markers. The ideal genetic assay would (1) employ highly polymorphic genetic markers for distinguishing among individuals; (2) use little tissue for analysing early life-history stages; and (3) require minimal investment in time and money for population level studies. From this perspective, DNA polymorphisms revealed by PCR amplification using random ten-base primers [Randomly Amplified Polymorphic DNA (PCR-RAPD) or Arbitrarily Primed DNA (AP-PCR)] have great potential. However, the evidence that RAPD/AP markers are both heritable and can be repeatably amplified remains controversial. This study characterizes patterns of inheritance and polymorphism of RAPD markers in the free-spawning, colonial marine hydrozoan Hydractinia symbiolongicarpus. In all cases, the amplification products were identical among extractions from the same clone. Of 56 primers screened, 13 had sufficient polymorphism and scoreability for an analysis of parentage and higher-order genetic relationships in three matings. These primers generated 156 unique amplification products (putative loci), of which 133 were polymorphic. All but four of these loci were inherited as dominant mendelian markers. Our study suggests that the presence of a marker represents a single allele at a locus; however, what appear to be single null alleles may actually comprise several segregating alleles. When the identity of neither parent was known a priori, inclusion (unique markers present in offspring and only one of the potential parents) proved to be more efficient than exclusion for assigning offspring to parents. The most powerful approach, however, was cluster analysis of all presence/absence information for the marker bands. Clustering avoided the pitfalls caused by the appearance of occasional nonparental bands, and constructed a hierarchical framework that correctly reflected all genealogical relationships.

Animals↗

PubMed2025

Comorbidity alters the genetic relationship between anxiety disorders and major depression.

BACKGROUND: Comorbid anxiety disorders (ANX) and major depression (MD) have worse clinical outcomes than either disorder alone. Analysis of genomic data based on comorbidity status may reveal more precise biological pathways and causal relationships with potential clinical implications. We investigated the genetic relationship between ANX and MD with and without mutual comorbidity. METHODS: We leveraged data from UK Biobank to perform disorder-specific genome-wide association studies (GWAS) of ANX-only (n=189,422) and MD-only (n=194,339) and generate polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa, n = 130,992) served to test the associations of PRS with diagnoses. MD and ANX GWAS, including comorbidities (MD-comorbid and ANX-comorbid), were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships. RESULTS: The MD-only PRS showed a stronger association with MD-only compared to ANX-only cases (Z=3.74; Padjusted=0.002); however, MD-comorbid PRS did not show a significant difference (Z=2.71; Padjusted=0.08). The genetic correlation between ANX-only and MD-only was 0.53, lower than between ANX-comorbid and MD-comorbid (0.90). ANX-only showed a causal relationship with MD-only (Padjusted=0.015), but not vice versa, and contrasted the bidirectional causal relationship (Padjusted=2.9e-12, and Padjusted=9.3e-06) when comorbidity was included. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for immune regulation pathways such as interleukin production. CONCLUSIONS: ANX and MD show more distinct genetics when comorbid cases are excluded, and ANX may be causal for MD. Disorder-specific genetic studies help uncover more relevant biological mechanisms and guide tailored clinical interventions.

Journal Article↗

PubMed2000

Segregation analysis of serum uric acid in the NHLBI Family Heart Study.

Segregation analysis was performed on the serum uric acid measurements from 523 randomly ascertained Caucasian families from the NHLBI Family Heart Study. Gender-specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analysis. Uric acid residuals were adjusted for age, age2, age3, body mass index (kg/m2), creatinine level, aspirin use (yes/no), total drinks (per week), HOMA insulin resistance index [(glucose * insulin)/22.5], diuretic use (yes/no), and triglyceride level. Sibling correlations (r=0.193) and parent-offspring correlations (r=0.217) were significantly different from zero, but these two familial correlations were not significantly different from one another. After adjustment for covariates, the heritability estimate for serum uric acid was 0.399. Segregation analysis rejected the "no major gene" model but was unable to discriminate between an "environmental" and a "Mendelian major gene" model. These results support the hypothesis that uric acid is a multifactorial trait possibly influenced by more than one major gene, modifying genes, and environmental factors.

Arteriosclerosis↗

PubMed1978

Inbreeding effects: evidence for a genetic system which regulates viability in Drosophila melanogaster populations.

Mating studies on individual couples of Drosophila melanogaster allowed the structure of inbred populations in terms of egg hatchability and egg-to-adult survival to be elucidated. The comparison between inbred (from brother-sister matings) and control (randomly crossed) populations distinguished between couples sensitive and insensitive to inbreeding. Mendelian ratios were observed for this "phenotypic trait" in the progeny of single couples. These ratios and a double mating experiment indicated that a gene or gene complex implicated in morphogenetic events blocked development during embryonic and larvo-pupal stages. The expression of this lethal gene in homozygous embryos depended on the genetic makeup of both parental flies, i.e., on male and female factors which act as regulatory components. Homozygous embryos which survived the first critical phase (from fertilization to hatching) continued to develop normally until the larvo-pupal period, when they died. Lethality was also modulated by the cytoplasmic composition of the parental eggs, as shown by taxonomic analysis and the double mating experiment. The results account for lethality throughout development due to inbreeding. They lead to an estimated genetic load from laying to adult stage of one "lethal equivalent".

Animals↗

PubMed2003

Robust asymptotic sampling theory for correlations in pedigrees.

Methods to unravel the genetic determinants of non-Mendelian diseases lie at the next frontier of statistical approaches for human genetics. It is generally agreed that, before proceeding with segregation or linkage analysis, the trait under study ought to be shown to exhibit familial correlation. By coding dichotomous traits as binary variables, a single robust approach in the estimation of pedigree correlations, rather than two distinct approaches, can be used to assess the potential heritability of a trait, and, latterly, to examine the mode of inheritance. The asymptotic theory to conduct hypothesis tests and confidence intervals for correlations among different members of nuclear families is well established but is applicable only if the nuclear families are independent. As a further contribution to the literature, we derive the asymptotic sampling distribution of correlations between random variables among arbitrary pairs of members in extended families for the Pearson product-moment estimator with generalized weights. This derivation is done without assuming normality of the traits. The sampling distribution is shown to be asymptotically normal to first order, and hence large-sample hypothesis tests and confidence intervals with estimates of the variances and correlation coefficients are proposed. Discussion concludes with an example and a suggestion for future research.

ABO Blood-Group System↗

PubMed1995

Segregation analysis of human red blood cell thiopurine methyltransferase activity.

Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine (6-MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6-MP and other thiopurine drugs. Variation of TPMT activity in the red blood cell (RBC) has been found to reflect activity differences in less accessible tissues. Previously reported qualitative analyses of inheritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present study we completed complex segregation analyses of RBC TPMT activity of 213 individuals in 49 families that were randomly ascertained through children in the Rochester, MN, public school system. We found clear evidence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gene with frequency of 0.94 for the allele conferring high enzyme activity. The genotype distributions of individuals who were homozygous for the low activity allele, heterozygous, and homozygous for the high activity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respectively, of the individuals in the sample. This major locus accounted for 66% of the total variance in untransformed RBC TPMT activity. Although there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect additional major locus or polygenic inheritance effects on the residual variance.

Adolescent↗

PubMed1993

Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity.

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2% of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50% of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2001

A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data.

The present study assesses the effects of genotyping errors on the type I error rate of a particular transmission/disequilibrium test (TDT(std)), which assumes that data are errorless, and introduces a new transmission/disequilibrium test (TDT(ae)) that allows for random genotyping errors. We evaluate the type I error rate and power of the TDT(ae) under a variety of simulations and perform a power comparison between the TDT(std) and the TDT(ae), for errorless data. Both the TDT(std) and the TDT(ae) statistics are computed as two times a log-likelihood difference, and both are asymptotically distributed as chi(2) with 1 df. Genotype data for trios are simulated under a null hypothesis and under an alternative (power) hypothesis. For each simulation, errors are introduced randomly via a computer algorithm with different probabilities (called "allelic error rates"). The TDT(std) statistic is computed on all trios that show Mendelian consistency, whereas the TDT(ae) statistic is computed on all trios. The results indicate that TDT(std) shows a significant increase in type I error when applied to data in which inconsistent trios are removed. This type I error increases both with an increase in sample size and with an increase in the allelic error rates. TDT(ae) always maintains correct type I error rates for the simulations considered. Factors affecting the power of the TDT(ae) are discussed. Finally, the power of TDT(std) is at least that of TDT(ae) for simulations with errorless data. Because data are rarely error free, we recommend that researchers use methods, such as the TDT(ae), that allow for errors in genotype data.

Alleles↗

PubMed2026

GFPT1 as a cross-ancestry validated target for degenerative spinal disease: genetic association in a Chinese cohort and functional characterization in zebrafish.

Degenerative spinal disease (DSD), including spinal stenosis and spondylosis, lacks effective pharmacological treatment. To identify druggable targets and assess cross-ancestry applicability, we integrate multi-omics analyses using Summary-data-based Mendelian Randomization (SMR), colocalization, and two-sample Mendelian randomization with European whole-blood, peripheral-blood, and CSF eQTL/pQTL datasets, followed by whole-genome sequencing (WGS) validation in a Chinese cohort. We identify 7 genes/proteins associated with spinal stenosis and 5 with spondylosis, with GFPT1, GPX1, and SERPINA1 shared by both. Two-sample MR further supports the causal associations of these targets with DSD. Phenome-wide MR prioritization selects GFPT1 and GPX1 as favorable candidates with no predicted adverse effects and potential beneficial effects on hypertension. In the Chinese cohort (67 lumbar spinal stenosis patients and 100 controls), WGS identifies 4 GFPT1 cis-eQTL loci (rs13016371, rs35392088, rs12997521, and rs13019789) associated with lumbar spinal stenosis risk; all risk alleles are linked to increased GFPT1 expression, and all 24 variant carriers show L4/L5 stenosis on imaging. Druggability analysis identifies IOX1 as the sole preclinical-stage compound targeting GFPT1, and molecular docking supports robust binding to GFPT1 (- 6.39 kcal/mol). Functional assays show that IOX1 directly inhibits GFPT1 enzymatic activity and induces fructose-6-phosphate accumulation. In zebrafish, IOX1 significantly rescues GFPT1-induced degenerative phenotypes. These findings establish GFPT1 as a cross-ancestry validated therapeutic target for DSD and nominate IOX1 as a promising disease-modifying candidate.

Animals↗

PubMed2004

Closing the gaps on human chromosome 19 revealed genes with a high density of repetitive tandemly arrayed elements.

The reported human genome sequence includes about 400 gaps of unknown sequence that were not found in the bacterial artificial chromosome (BAC) and cosmid libraries used for sequencing of the genome. These missing sequences correspond to approximately 1% of euchromatic regions of the human genome. Gap filling is a laborious process because it relies on analysis of random clones of numerous genomic BAC or cosmid libraries. In this work we demonstrate that closing the gaps can be accelerated by a selective recombinational capture of missing chromosomal segments in yeast. The use of both methodologies allowed us to close the four remaining gaps on the human chromosome 19. Analysis of the gap sequences revealed that they contain several abnormalities that could result in instability of the sequences in microbe hosts, including large blocks of micro- and minisatellites and a high density of Alu repeats. Sequencing of the gap regions, in both BAC and YAC forms, allowed us to generate a complete sequence of four genes, including the neuronal cell signaling gene SCK1/SLI. The SCK1/SLI gene contains a record number of minisatellites, most of which are polymorphic and transmitted through meiosis following a Mendelian inheritance. In conclusion, the use of the alternative recombinational cloning system in yeast may greatly accelerate work on closing the remaining gaps in the human genome (as well as in other complex genomes) to achieve the goal of annotation of all human genes.

Alu Elements↗