Parent-offspring Trios Research Articles

Assessing and comparison of different machine learning methods in parent-offspring trios for genotype imputation

Genotype imputation is an important tool for prediction of unknown genotypes for both unrelated individuals and parent-offspring trios. Several imputation methods are available and can either employ universal machine learning methods, or deploy algorithms dedicated to infer missing genotypes. In this research the performance of eight machine learning methods: Support Vector Machine, K-Nearest Neighbors, Extreme Learning Machine, Radial Basis Function, Random Forest, AdaBoost, LogitBoost, and TotalBoost compared in terms of the imputation accuracy, computation time and the factors affecting imputation accuracy. The methods employed using real and simulated datasets to impute the un-typed SNPs in parent-offspring trios. The tested methods show that imputation of parent-offspring trios can be accurate. The Random Forest and Support Vector Machine were more accurate than the other machine learning methods. The TotalBoost performed slightly worse than the other methods.The running times were different between methods. The ELM was always most fast algorithm. In case of increasing the sample size, the RBF requires long imputation time.The tested methods in this research can be an alternative for imputation of un-typed SNPs in low missing rate of data. However, it is recommended that other machine learning methods to be used for imputation.

Disentangling the associations between parental BMI and offspring body composition using the four-component model.

ABSTRACTObjectivesThis study sets out to investigate the intergenerational associations between the body mass index (BMI) of parents and the body composition of their offspring.MethodsThe cross‐sectional data were analyzed for 511 parent–offspring trios from London and south‐east England. The offspring were aged 5–21 years. Parental BMI was obtained by recall and offspring fat mass and lean mass were obtained using the four‐component model. Multivariable regression analysis, with multiple imputation for missing paternal values was used. Sensitivity analyses for levels of non‐paternity were conducted.ResultsA positive association was seen between parental BMI and offspring BMI, fat mass index (FMI), and lean mass index (LMI). The mother's BMI was positively associated with the BMI, FMI, and LMI z‐scores of both daughters and sons and of a similar magnitude for both sexes. The father's BMI showed similar associations to the mother's BMI, with his son's BMI, FMI, and LMI z‐scores, but no association with his daughter. Sensitivity tests for non‐paternity showed that maternal coefficients remained greater than paternal coefficients throughout but there was no statistical difference at greater levels of non‐paternity.ConclusionsWe found variable associations between parental BMI and offspring body composition. Associations were generally stronger for maternal than paternal BMI, and paternal associations appeared to differ between sons and daughters. In this cohort, the mother's BMI was statistically significantly associated with her child's body composition but the father's BMI was only associated with the body composition of his sons. Am. J. Hum. Biol. 28:524–533, 2016. © 2016 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc.

Disease and Polygenic Architecture: Avoid Trio Design and Appropriately Account for Unscreened Control Subjects for Common Disease

Genome-wide association studies (GWASs) are an optimal design for discovery of disease risk loci for diseases whose underlying genetic architecture includes many common causal loci of small effect (a polygenic architecture). We consider two designs that deserve careful consideration if the true underlying genetic architecture of the trait is polygenic: parent-offspring trios and unscreened control subjects. We assess these designs in terms of quantification of the total contribution of genome-wide genetic markers to disease risk (SNP heritability) and power to detect an associated risk allele. First, we show that trio designs should be avoided when: (1) the disease has a lifetime risk > 1%; (2) trio probands are ascertained from families with more than one affected sibling under which scenario the SNP heritability can drop by more than 50% and power can drop as much as from 0.9 to 0.15 for a sample of 20,000 subjects; or (3) assortative mating occurs (spouse correlation of the underlying liability to the disorder), which decreases the SNP heritability but not the power to detect a single locus in the trio design. Some studies use unscreened rather than screened control subjects because these can be easier to collect; we show that the estimated SNP heritability should then be scaled by dividing by (1- K × u)(2) for disorders with population prevalence Kand proportion of unscreened control subjects u. When omitting to scale appropriately, the SNP heritability of, for example, major depressive disorder (K = 0.15) would be underestimated by 28% when none of the control subjects are screened.

Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder.

Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

A computational method for genotype calling in family-based sequencing data.

BackgroundAs sequencing technologies can help researchers detect common and rare variants across the human genome in many individuals, it is known that jointly calling genotypes across multiple individuals based on linkage disequilibrium (LD) can facilitate the analysis of low to modest coverage sequence data. However, genotype-calling methods for family-based sequence data, particularly for complex families beyond parent-offspring trios, are still lacking.ResultsIn this study, first, we proposed an algorithm that considers both linkage disequilibrium (LD) patterns and familial transmission in nuclear and multi-generational families while retaining the computational efficiency. Second, we extended our method to incorporate external reference panels to analyze family-based sequence data with a small sample size. In simulation studies, we show that modeling multiple offspring can dramatically increase genotype calling accuracy and reduce phasing and Mendelian errors, especially at low to modest coverage. In addition, we show that using external panels can greatly facilitate genotype calling of sequencing data with a small number of individuals. We applied our method to a whole genome sequencing study of 1339 individuals at ~10X coverage from the Minnesota Center for Twin and Family Research.ConclusionsThe aggregated results show that our methods significantly outperform existing ones that ignore family constraints or LD information. We anticipate that our method will be useful for many ongoing family-based sequencing projects. We have implemented our methods efficiently in a C++ program FamLDCaller, which is available from http://www.pitt.edu/~wec47/famldcaller.html.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-0880-5) contains supplementary material, which is available to authorized users.

Comparison of three boosting methods in parent-offspring trios for genotype imputation using simulation study.

BackgroundGenotype imputation is an important process of predicting unknown genotypes, which uses reference population with dense genotypes to predict missing genotypes for both human and animal genetic variations at a low cost. Machine learning methods specially boosting methods have been used in genetic studies to explore the underlying genetic profile of disease and build models capable of predicting missing values of a marker.MethodsIn this study strategies and factors affecting the imputation accuracy of parent-offspring trios compared from lower-density SNP panels (5 K) to high density (10 K) SNP panel using three different Boosting methods namely TotalBoost (TB), LogitBoost (LB) and AdaBoost (AB). The methods employed using simulated data to impute the un-typed SNPs in parent-offspring trios. Four different datasets of G1 (100 trios with 5 k SNPs), G2 (100 trios with 10 k SNPs), G3 (500 trios with 5 k SNPs), and G4 (500 trio with 10 k SNPs) were simulated. In four datasets all parents were genotyped completely, and offspring genotyped with a lower density panel.ResultsComparison of the three methods for imputation showed that the LB outperformed AB and TB for imputation accuracy. The time of computation were different between methods. The AB was the fastest algorithm. The higher SNP densities resulted the increase of the accuracy of imputation. Larger trios (i.e. 500) was better for performance of LB and TB.ConclusionsThe conclusion is that the three methods do well in terms of imputation accuracy also the dense chip is recommended for imputation of parent-offspring trios.

Mitochondrial Complex III Deficiency with Ketoacidosis and Hyperglycemia Mimicking Neonatal Diabetes.

Hyperglycemia is a rare presenting symptom of mitochondrial disorders. We report a case of a young girl who presented shortly after birth with ketoacidosis, hyperlactatemia, hyperammonemia, and insulin-responsive hyperglycemia. Initial metabolic work-up suggested mitochondrial dysfunction. Given our patient's unusual presentation, whole-exome sequencing (WES) was performed on the parent-offspring trio. The patient was homozygous for the c.643C>T (p.Leu215Phe) variant in CYC1, a nuclear gene which encodes cytochrome c 1 , a subunit of respiratory chain complex III. Variants in this gene have only been previously reported in two patients with similar presentation, one of whom carries the same variant as our patient who is also of Sri Lankan origin.Primary complex III deficiencies are rare and its phenotypes can vary significantly, even among patients with the same genotype.

Joint detection of copy number variations in parent-offspring trios.

Whole genome sequencing (WGS) of parent-offspring trios is a powerful approach for identifying disease-associated genes via detecting copy number variations (CNVs). Existing approaches, which detect CNVs for each individual in a trio independently, usually yield low-detection accuracy. Joint modeling approaches leveraging Mendelian transmission within the parent-offspring trio can be an efficient strategy to improve CNV detection accuracy. In this study, we developed TrioCNV, a novel approach for jointly detecting CNVs in parent-offspring trios from WGS data. Using negative binomial regression, we modeled the read depth signal while considering both GC content bias and mappability bias. Moreover, we incorporated the family relationship and used a hidden Markov model to jointly infer CNVs for three samples of a parent-offspring trio. Through application to both simulated data and a trio from 1000 Genomes Project, we showed that TrioCNV achieved superior performance than existing approaches. The software TrioCNV implemented using a combination of Java and R is freely available from the website at https://github.com/yongzhuang/TrioCNV CONTACT: ydwang@hit.edu.cn Supplementary data are available at Bioinformatics online.

Transmission of energy-saving efficiency from obese parents to their offspring: the Korean National Health and Nutrition Examination Survey 2007–2011

Concerns of a growing obesity epidemic have increased since the association between obesity in parents and that in offspring was reported. However, the evidence regarding whether the energy-saving efficiency of obese parents is conveyed to their offspring and the duration of the expression of such transmitted efficiency is limited. We included 7647 matching sets of parent-offspring trios from South Korea. Multiple linear regression models were performed to estimate the energy-saving efficiency, as assessed by the associations between energy intake and obesity-related indices (waist-to-height ratio, waist circumference and body mass index z-score), and to compare the energy-saving efficiency of offspring of obese and non-obese parents. All analyses were based on a complex sample design and were stratified by gender and age. We identified a parental influence on obesity, that is, the more obese the parent, the higher the obesity-related indices of their offspring, in both genders and all age groups. The energy-saving efficiency of child offspring was highest when both parents were obese and lowest when both were non-obese; this difference was significant (P<0.05) with regard to the energy-saving efficiency of all types of intake studied, except fat. However, the energy-saving efficiency of obese and non-obese parents did not differ when their offspring were adolescents and adults. The critical window for transmission of energy-saving efficiency is limited to childhood. These findings suggest that children of obese parents should be more emphatically advised to maintain a balanced diet and to engage in regular physical activity.

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease genes has involved analysis of large, often consanguineous, multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of novel dominant causes of rare, genetically heterogenous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios 1,2. Here we analysed 4,125 families with diverse, rare, genetically heterogeneous developmental disorders and identified four novel autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (identifying probands with rare biallelic putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population, and (ii) the phenotypic similarity of patients with the same recessive candidate gene. This new paradigm promises to catalyse discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations, and those caused predominantly by compound heterozygous genotypes.

Parental determinants of metabolic syndrome among adolescent Asian Indians: A cross-sectional analysis of parent-offspring trios.

The aim of the present study was to investigate the relationship between parental metabolic syndrome (MS) and the risk of MS and associated abnormalities in adolescent offspring. This cross-sectional study was performed on 304 adolescents (12-16 years; 236 children with at least one parent and 124 father-mother-child trios) recruited from four schools representing different socioeconomic strata from Vellore, India. Anthropometric data was collected and blood pressure, blood glucose, and lipids were measured. The prevalence of MS in adolescent offspring, fathers, and mothers was 3.3%, 52.5%, and 48.7% respectively. The most commonly observed metabolic abnormality among adolescents was lower high-density lipoprotein. Maternal waist circumference (WC) was strongly correlated with adolescent body mass index (P = 0.007), WC (P < 0.001), serum triglycerides (P = 0.02), and systolic (P = 0.005) and diastolic (P = 0.01) blood pressure. Maternal MS status was significantly associated with a greater risk of central obesity (WC odds ratio [OR] 2.02; 95% confidence interval [CI] 1.21-3.17) in offspring. Both parents having MS conferred a significant effect on the child's WC (OR 1.21; 95% CI 1.72-2.07) and increased risk of MS (OR 6.19; 95% CI 1.64-23.26). This study highlights the possible heritable parental components that may contribute to the MS phenotype in offspring: MS in adolescent offspring is related to parental MS status, and maternal traits reflect offspring adiposity and metabolic traits more strongly than paternal factors. Therefore, adolescent children of parents with MS should be targets for primordial prevention of cardiometabolic disease.

De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent–offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.

Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation

De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. To determine the contribution of post-zygotic events to de novo mutations, we analyzed a set of 107 de novo mutations in 50 parent-offspring trios. Using four different sequencing techniques, we found that 7 (6.5%) of these presumed germline de novo mutations were in fact present as mosaic mutations in the blood of the offspring and were therefore likely to have occurred post-zygotically. Furthermore, genome-wide analysis of "de novo" variants in the proband led to the identification of 4/4,081 variants that were also detectable in the blood of one of the parents, implying parental mosaicism as the origin of these variants. Thus, our results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents.

Genotyping of geographically diverse Druze trios reveals substructure and a recent bottleneck.

Druze individuals rarely marry outside their faith (often practicing consanguinity) and are thus believed to form a genetic isolate. To comprehensively characterize the genetic structure of the Druze population, we recruited and genotyped 40 parent-offspring trios from the Upper Galilee in Israel and the Golan Heights, attempting to capture different extended families (clans) across various geographical locations. Principal component (PC) and ADMIXTURE analyses demonstrated that Druze are close to, yet distinct from, other Middle-Eastern groups (Bedouins and Palestinians), supporting the Druze's Middle-Eastern origin and their recent genetic isolation. Reconstruction of the Druze demographic history using identical-by-descent (IBD) segments suggested an ≈15-fold reduction in population size taking place ≈22-47 generations ago, close to the documented time of the foundation of the Druze faith at the 11th century. Combining the Galilee and Golan Druze genotypes with previously published data on Druze from the Carmel (Israel) and Lebanon demonstrated that all four Druze communities are genetically distinct. The Lebanese group shared less IBD segments (within the group and with other groups) compared with the Israeli Druze and showed higher heterozygosity (suggesting less consanguinity), but was less diverse in PC space. These findings suggest complex recent and ancient demographic history of the Druze population.

Neck/upper back and low back pain in parents and their adult offspring: Family linkage data from the Norwegian HUNT Study.

Chronic pain in the neck and low back is highly prevalent. Although heritable components have been identified, knowledge about generational transmission of spinal pain between parents and their adult offspring is sparse. This study examined the intergenerational association of spinal pain using data from 11,081 parent-offspring trios participating in the population-based HUNT Study in Norway. Logistic regression was used to calculate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for offspring spinal pain associated with parental spinal pain. In total, 3654 (33%) offspring reported spinal pain at participation. Maternal and paternal spinal pain was consistently associated with higher ORs for offspring spinal pain. The results suggest a slightly stronger association for parental multilevel spinal pain (i.e., both neck/upper back pain and low back pain) than for pain localized to the neck/upper back or low back. Multilevel spinal pain in both parents was associated with ORs of 2.6 (95% CI, 2.1-3.3), 2.4 (95% CI, 1.9-3.1) and 3.1 (95% CI, 2.2-4.4) for offspring neck/upper back, low back and multilevel spinal pain, respectively. Parental chronic spinal pain was consistently associated with increased occurrence of chronic spinal pain in their adult offspring, and this association was particularly strong for multilevel spinal pain.

Parental chronic pain in relation to chronic pain in their adult offspring: family-linkage within the HUNT Study, Norway.

BackgroundLittle is known about the association between parental chronic musculoskeletal pain (CMP) and occurrence of CMP in the adult offspring. The main objective of this study was to assess the parent-offspring association of CMP, and also to examine possible modifying effects of age and sex.MethodsThe study includes 11 248 parent-offspring trios from the Norwegian HUNT Study with information on parental CMP obtained in 1995–97 and offspring CMP obtained in 2006–08. Logistic regression was used to calculate adjusted odds ratios (ORs) for offspring CMP associated with parental CMP.ResultsMaternal and paternal CMP was associated with 20-40% increased odds of CMP in sons and daughters. Both sons and daughters had an OR of 1.6 (95% CI 1.4 to 1.9) when both parents reported CMP, compared to when none of the parents had CMP. Restricting the analyses to parental CMP that was associated with limited work ability and leisure time activity did not change the strength of the association. Further, analyses stratified by parental age ±65 years showed no clear difference in the estimated associations, and there was no evidence of interaction for parental sex (P ≥ 0.39) or offspring age ±40 years (P ≥ 0.26).ConclusionsThis large family-linkage study show that maternal and paternal CMP are positively associated with CMP in the adult offspring, irrespective of parental and offspring age, and that the associations are strongest when both parents have CMP. Although the high prevalence of CMP in both parents and offspring suggests that not all cases are clinically relevant, the results suggest that chronic pain has a heritable component.

Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive–compulsive disorder

Despite compelling evidence for major genetic contributions to the etiology of obsessive–compulsive disorder (OCD), few genetic variants have been consistently associated with this debilitating illness. Molecular genetic studies in children and adolescents with OCD are of particular interest, since early onset of the disease has been observed to be associated with increased familiality. We replicate here for the first time in early-onset OCD patients, a previously reported association of OCD with the common gain-of-function LA allele at the serotonin transporter linked polymorphic region known as 5-HTTLPR in a collection of parent-offspring trios. The present meta-analysis of this recently refined serotonin transporter gene variant revealed further support for the LA allele conferring increased genetic susceptibility to OCD. We conclude that the 5-HTTLPR is currently the single best supported risk variant for OCD, in regards of early-onset OCD, albeit of modest effect size and the possibility that the conferred risk might not be specific to OCD.

Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications

High-throughput DNA sequencing technology has transformed genetic research and is starting to make an impact on clinical practice. However, analyzing high-throughput sequencing data remains challenging, particularly in clinical settings where accuracy and turnaround times are critical. We present a new approach to this problem, implemented in a software package called Platypus. Platypus achieves high sensitivity and specificity for SNPs, indels and complex polymorphisms by using local de novo assembly to generate candidate variants, followed by local realignment and probabilistic haplotype estimation. It is an order of magnitude faster than existing tools and generates calls from raw aligned read data without preprocessing. We demonstrate the performance of Platypus in clinically relevant experimental designs by comparing with SAMtools and GATK on whole-genome and exome-capture data, by identifying de novo variation in 15 parent-offspring trios with high sensitivity and specificity, and by estimating human leukocyte antigen genotypes directly from variant calls.

Use of population structure and parentage analyses to elucidate the spread of native cultivars of Japanese chestnut

The Japanese chestnut (Castanea crenata Siebold et Zucc.) is naturally distributed throughout Japan and is cultivated for its fruit (nuts) throughout the country. Many native cultivars have cultivation records going back more than 100 years. Researchers have speculated that native cultivars that originated in the Tanba region, the most important region of cultivation, were spread throughout Japan. To clarify the breeding history and spreading pattern of Japanese chestnut cultivars, we estimated the population structure of a set of 60 native chestnut cultivars via hierarchical clustering and Bayesian model-based clustering. Both analyses gave similar results. The cultivars were divided into two main clusters: one with cultivars from the Tanba region, the other with cultivars from other areas of Japan. However, there were some exceptions to this pattern, suggesting that propagation of clones and seeds by humans was a part of the spreading process. Additionally, parent–offspring relationships were estimated from the data obtained for 175 simple sequence repeat markers. Out of the 60 genotypes, nine putative parent–offspring pairs and eight putative parent–offspring trios were identified. These results suggest that native cultivars are likely to have been selected from crosses of older native cultivars. In particular, some native cultivars from outside the Tanba region had parent–offspring relationships with cultivars from the Tanba region. This result suggests that cultivars from outside the Tanba region had been crossed with cultivars from the Tanba region and then selected as a means of introducing favorable traits from the Tanba cultivars.

De novo mutations in HCN1 cause early infantile epileptic encephalopathy.

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.