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1.
Behav Genet ; 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33582897

RESUMO

The Classical Twin Method (CTM) compares the similarity of monozygotic (MZ) twins with that of dizygotic (DZ) twins to make inferences about the relative importance of genes and environment in the etiology of individual differences. The design has been applied to thousands of traits across the biomedical, behavioral and social sciences and is arguably the most widely used natural experiment known to science. The fundamental assumption of the CTM is that trait relevant environmental covariation within MZ pairs is the same as that found within DZ pairs, so that zygosity differences in within-pair variance must be due to genetic factors uncontaminated by the environment. This equal environments assumption (EEA) has been, and still is hotly contested, and has been mentioned as a possible contributing factor to the missing heritability conundrum. In this manuscript, we introduce a new model for testing the EEA, which we call the Augmented Classical Twin Design which uses identity by descent (IBD) sharing between DZ twin pairs to estimate separate environmental variance components for MZ and DZ twin pairs, and provides a test of whether these are equal. We show through simulation that given large samples of DZ twin pairs, the model provides unbiased estimates of variance components and valid tests of the EEA under strong assumptions (e.g. no epistatic variance, IBD sharing in DZ twins estimated accurately etc.) which may not hold in reality. Sample sizes in excess of 50,000 DZ twin pairs with genome-wide genetic data are likely to be required in order to detect substantial violations of the EEA with moderate power. Consequently, we recommend that the Augmented Classical Twin Design only be applied to datasets with very large numbers of DZ twin pairs (> 50,000 DZ twin pairs), and given the strong assumptions relating to the absence of epistatic variance, appropriate caution be exercised regarding interpretation of the results.

2.
Behav Genet ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387132

RESUMO

Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to three exemplar phenotypes: offspring birth weight, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).

3.
Behav Genet ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33454873

RESUMO

Disaggregation and estimation of genetic effects from offspring and parents has long been of interest to statistical geneticists. Recently, technical and methodological advances have made the genome-wide and loci-specific estimation of direct offspring and parental genetic nurture effects more possible. However, unbiased estimation using these methods requires datasets where both parents and at least one child have been genotyped, which are relatively scarce. Our group has recently developed a method and accompanying software (IMPISH; Hwang et al. in PLoS Genet 16:e1009154, 2020) which is able to impute missing parental genotypes from observed data on sibships and estimate their effects on an offspring phenotype conditional on the effects of genetic transmission. However, this method is unable to disentangle maternal and paternal effects, which may differ in magnitude and direction. Here, we introduce an extension to the original IMPISH routine which takes advantage of all available nuclear families to impute parent-specific missing genotypes and obtain asymptotically unbiased estimates of genetic effects on offspring phenotypes. We apply this this method to data from related individuals in the UK Biobank, showing concordance with previous estimates of maternal genetic effects on offspring birthweight. We also conduct the first GWAS jointly estimating offspring-, maternal-, and paternal-specific genetic effects on body-mass index.

4.
J Dev Orig Health Dis ; : 1-6, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33272351

RESUMO

Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms; where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.

5.
Int J Epidemiol ; 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33347560

RESUMO

BACKGROUND: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal. METHODS: We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels. RESULTS: We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [-0.051 (-0.100, -0.003)]. CONCLUSIONS: Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.

6.
PLoS Genet ; 16(10): e1009154, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33104719

RESUMO

Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to their children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at individual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset conditions, can be estimated at individual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating "virtual" mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We apply our approach to 19066 sibling pairs from the UK Biobank and show that a polygenic score consisting of imputed parental educational attainment SNP dosages is strongly related to offspring educational attainment even after correcting for offspring genotype at the same loci. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH (IMputing Parental genotypes In Siblings and Half Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.

7.
Nat Commun ; 11(1): 5404, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106479

RESUMO

There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.


Assuntos
Peso ao Nascer , Doenças Cardiovasculares/genética , Herança Materna , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Análise da Randomização Mendeliana , Noruega/epidemiologia , Herança Paterna , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
8.
Alzheimers Dement (Amst) ; 12(1): e12108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005726

RESUMO

Introduction: Hearing loss has been identified as the potentially largest modifiable risk factor for Alzheimer's disease (AD), estimated to account for a similar increase in AD risk as the apolipoprotein E (APOE) gene. Methods: We investigated the genetic relationship between hearing loss and AD, and sought evidence for a causal relationship. Results: We found a significant genetic overlap between hearing impairment and AD and a polygenic risk score for AD was able to significantly predict hearing loss in an independent cohort. Additionally, regions of the genome involved in inflammation were identified to be shared between hearing difficulty and AD. However, causality tests found no significant evidence of a causal relationship between these traits in either direction. Discussion: Overall, these results show that the relationship between hearing difficulty and AD may, in part, be due to shared genes and immune response pathways between the traits. However, currently available data do not support a causal relationship.

9.
Behav Genet ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989645

RESUMO

The International Statistical Genetics Workshop (commonly referred to as the "Boulder Workshop") has been held annually in Boulder, Colorado almost every year since 1990. A staple feature of each workshop has been the presence of a "question box" (either a physical box or an online virtual one) where workshop participants are given the opportunity of asking questions to the faculty. In this manuscript, we have compiled a list of ten "classic" questions that have appeared in one form or another across multiple workshops and our attempts at answering them.

10.
Twin Res Hum Genet ; 23(4): 204-213, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32755526

RESUMO

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

11.
Nat Commun ; 11(1): 3519, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665587

RESUMO

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.


Assuntos
Análise da Randomização Mendeliana/métodos , Índice de Massa Corporal , Epidemiologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
12.
PLoS Med ; 17(7): e1003152, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614825

RESUMO

BACKGROUND: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. METHODS AND FINDINGS: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. CONCLUSIONS: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.


Assuntos
Programas de Rastreamento/métodos , Herança Multifatorial , Fraturas por Osteoporose/genética , Fraturas por Osteoporose/prevenção & controle , Medição de Risco/métodos , Idoso , Densidade Óssea , Calcâneo/diagnóstico por imagem , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Calcanhar/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Fatores de Risco , Ultrassonografia , Reino Unido
13.
Nat Commun ; 11(1): 2797, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493999

RESUMO

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Distribuição da Gordura Corporal , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Trombospondinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/genética , Adulto , Alelos , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Doxiciclina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Células-Tronco/metabolismo , Trombospondinas/genética , Relação Cintura-Quadril , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
14.
Twin Res Hum Genet ; 23(2): 96-97, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32423503

RESUMO

Blood cell concentrations for most cell types are highly heritable. Data from Nick Martin's twin registry provided much of the data for the early heritability and linkage studies of blood cell related traits and have contributed significantly to more recent genomewide association studies that have successfully identified individual genetic loci.

15.
Am J Respir Crit Care Med ; 202(5): 700-707, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32396775

RESUMO

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.


Assuntos
Aldosterona/sangue , Ácido Ascórbico/sangue , Hidrocortisona/farmacocinética , Choque Séptico/tratamento farmacológico , Idoso , Anti-Inflamatórios/farmacocinética , Austrália/epidemiologia , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Choque Séptico/sangue , Choque Séptico/mortalidade , Taxa de Sobrevida/tendências , Resultado do Tratamento
17.
Am J Med Genet B Neuropsychiatr Genet ; 183(5): 258-267, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32356930

RESUMO

It is unclear to what extent parental influences on the development of internalizing problems in offspring are explained by indirect genetic effects, reflected in the environment provided by the parent, in addition to the genes transmitted from parent to child. In this study, these effects were investigated using two innovative methods in a large birth cohort. Using maternal-effects genome complex trait analysis (M-GCTA), the effects of offspring genotype, maternal or paternal genotypes, and their covariance on offspring internalizing problems were estimated in 3,801 mother-father-child genotyped trios. Next, estimated genetic correlations within pedigree data, including 10,688 children, were used to estimate additive genetic effects, maternal and paternal genetic effects, and a shared family effect using linear mixed effects modeling. There were no significant maternal or paternal genetic effects on offspring anxiety or depressive symptoms at age 8, beyond the effects transmitted via the genetic pathway between parents and children. However, indirect maternal genetic effects explained a small, but nonsignificant, proportion of variance in childhood depressive symptoms in both the M-GCTA (~4%) and pedigree (~8%) analyses. Our results suggest that parental effects on offspring internalizing problems are predominantly due to transmitted genetic variants, rather than the indirect effect of parental genes via the environment.

18.
J Bone Miner Res ; 35(7): 1224-1235, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32163637

RESUMO

Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use or by a general effect of lipid lowering. We utilized 400 single-nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (ß = -0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% confidence interval [CI] = -0.08 to -0.04; p = 4 × 10-6 ), total body BMD (ß = -0.05, 95% CI = -0.08 to -0.01, p = 6 × 10-3 ) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (ß = -0.083; -0.132 to -0.034; p = .001) to those excluding these SNPs (ß = -0.063; -0.090 to -0.036; p = 8 × 10-6 ). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis. © 2020 American Society for Bone and Mineral Research.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32122917

RESUMO

Most Mendelian randomization (MR) studies published in the literature to date have involved analyses of unrelated, putatively independent sets of individuals. However, estimates obtained from these sorts of studies are subject to a range of biases including dynastic effects, assortative mating, residual population stratification, and horizontal pleiotropy. The inclusion of related individuals in MR studies can help control for and, in some cases, estimate the effect of these biases on causal parameters. In this review, we discuss these biases, how they can affect MR studies, and describe three sorts of family-based study designs that can be used to control for them. We conclude that including family information from related individuals is not only possible given the world's existing twin, birth, and large-scale population-based cohorts, but likely to reap rich rewards in understanding the etiology of complex traits and diseases in the near future.

20.
Behav Genet ; 50(1): 51-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493278

RESUMO

There is increasing interest within the genetics community in estimating the relative contribution of parental genetic effects on offspring phenotypes. Here we describe the user-friendly M-GCTA software package used to estimate the proportion of phenotypic variance explained by maternal (or alternatively paternal) and offspring genotypes on offspring phenotypes. The tool requires large studies where genome-wide genotype data are available on mother- (or alternatively father-) offspring pairs. The software includes several options for data cleaning and quality control, including the ability to detect and automatically remove cryptically related pairs of individuals. It also allows users to construct genetic relationship matrices indexing genetic similarity across the genome between parents and offspring, enabling the estimation of variance explained by maternal (or alternatively paternal) and offspring genetic effects. We evaluated the performance of the software using a range of data simulations and estimated the computing time and memory requirements. We demonstrate the use of M-GCTA on previously analyzed birth weight data from two large population based birth cohorts, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother and Child Cohort Study (MoBa). We show how genetic variation in birth weight is predominantly explained by fetal genetic rather than maternal genetic sources of variation.


Assuntos
Peso ao Nascer/genética , Previsões/métodos , Criança , Estudos de Coortes , Simulação por Computador , Pai , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estudos Longitudinais , Masculino , Herança Materna/fisiologia , Modelos Genéticos , Mães , Pais , Herança Paterna/fisiologia , Fenótipo , Software
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