scholarly journals Genetics of early growth traits

2020 ◽  
Vol 29 (R1) ◽  
pp. R66-R72
Author(s):  
Diana L Cousminer ◽  
Rachel M Freathy
Keyword(s):  
Birth Weight ◽  
Health Outcomes ◽  
Fetal Growth ◽  
Association Studies ◽  
Later Life ◽  
Early Growth ◽  
Mr Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Contributions

Abstract In recent years, genome-wide association studies have shed light on the genetics of early growth and its links with later-life health outcomes. Large-scale datasets and meta-analyses, combined with recently developed analytical methods, have enabled dissection of the maternal and fetal genetic contributions to variation in birth weight. Additionally, longitudinal approaches have shown differences between the genetic contributions to infant, childhood and adult adiposity. In contrast, studies of adult height loci have shown strong associations with early body length and childhood height. Early growth-associated loci provide useful tools for causal analyses: Mendelian randomization (MR) studies have provided evidence that early BMI and height are causally related to a number of adult health outcomes. We advise caution in the design and interpretation of MR studies of birth weight investigating effects of fetal growth on later-life cardiometabolic disease because birth weight is only a crude indicator of fetal growth, and the choice of genetic instrument (maternal or fetal) will greatly influence the interpretation of the results. Most genetic studies of early growth have to date centered on European-ancestry participants and outcomes measured at a single time-point, so key priorities for future studies of early growth genetics are aggregation of large samples of diverse ancestries and longitudinal studies of growth trajectories.

scholarly journals Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

2021 ◽  
Author(s):  
Robin N Beaumont ◽  
Isabelle K Mayne ◽  
Rachel M Freathy ◽  
Caroline F Wright
Keyword(s):  
Birth Weight ◽  
Statistical Power ◽  
Developmental Disorders ◽  
Association Studies ◽  
Later Life ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Causal Genes

Abstract Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.

Trans-Ethnic Meta-Analysis of Interactions Between Genetics and Early-Life Socioeconomic Context on Memory Performance and Decline in Older Americans

2021 ◽  
Author(s):  
Jessica D Faul ◽  
Minjung Kho ◽  
Wei Zhao ◽  
Kalee E Rumfelt ◽  
Miao Yu ◽  
...  
Keyword(s):  
Parental Education ◽  
Association Studies ◽  
Memory Performance ◽  
Meta Analysis ◽  
African Ancestry ◽  
Later Life ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Socioeconomic Context

Abstract Background Later-life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Methods Using gene-based tests (interaction sequence kernel association test [iSKAT]/iSKAT optimal unified test), we examined whether common and/or rare exonic variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N = 10 468) and African ancestry (AA, N = 2 252) participants from the Health and Retirement Study. Results Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father’s education by solute carrier family 24 member 4 [SLC24A4] in AA) were not significant after multiple testing correction (false discovery rate [FDR] < .05). In trans-ethnic meta-analysis, 2 genes interacted with childhood socioeconomic context (FDR < .05): mother’s education by membrane-spanning 4-domains A4A (MS4A4A) on memory performance, and father’s education by SLC24A4 on memory decline. Both interactions remained significant (p < .05) after adjusting for respondent’s own educational attainment, apolipoprotein-ε4 allele (APOE ε4) status, lifestyle factors, body mass index, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Conclusions Examination of common and rare variants in genes discovered through genome-wide association studies shows that childhood context may interact with key gene regions to jointly impact later-life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

Genetic influences on the association between fetal growth and susceptibility to type 2 diabetes

2010 ◽  
Vol 1 (2) ◽  
pp. 96-105 ◽  
Author(s):  
B. M. Shields ◽  
R. M. Freathy ◽  
A. T. Hattersley
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Fetal Growth ◽  
Association Studies ◽  
Single Gene ◽  
Genome Wide Association Studies ◽  
The Impact

The fetal insulin hypothesis proposes that low birth weight and susceptibility to type 2 diabetes (T2D) could both be two phenotypes of the same genotype. Insulin is a key growth factor in utero, and T2D is characterized by insulin resistance and/or beta-cell dysfunction. Therefore, genetic variants impacting on insulin secretion and action are likely to alter both fetal growth and susceptibility to T2D. There are three lines of evidence in support of this hypothesis. (1) Studies of rare monogenic diabetes have shown mutations in a single gene, such as GCK or KCNJ11, can cause diabetes by reducing insulin secretion, and these mutations are also associated with reduced birth weight. (2) Epidemiological studies have indicated that children born to fathers with diabetes are born smaller. As the father cannot influence the intrauterine environment, this association is likely to reflect genes inherited by the fetus from the father. (3) The most compelling evidence comes from recent genome-wide association studies. Variants in the CDKAL1 and HHEX-IDE genes that predispose to diabetes, if present in the fetus, are associated with reduced birth weight. These data provide evidence for a genetic contribution to the association between low birth weight and susceptibility to T2D. This genetic background is important to take into consideration when investigating the impact of environmental determinants and developing strategies for intervention and prevention.

scholarly journals Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics

2015 ◽  
Author(s):  
Robin N Beaumont ◽  
Nicole M Warrington ◽  
Alana Cavadino ◽  
Jessica Tyrrell ◽  
Michael Nodzenski ◽  
...  
Keyword(s):  
Birth Weight ◽  
Fetal Growth ◽  
Association Studies ◽  
Genetic Effects ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Maternal Genotype ◽  
Maternal Determinants ◽  
Gestational Duration

AbstractGenome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about how maternal genetic variation influences fetal growth. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth.We meta-analysed GWAS data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects.Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9 and CYP3A7) showed evidence of association with offspring birth weight at P<5x10-8. The SEM analyses showed at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration.The identified associations indicate effects of maternal glucose, cytochrome P450 activity and gestational duration, and potential effects of maternal blood pressure and immune function on fetal growth. Further characterization of these associations, for example in mechanistic and causal analyses, will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

scholarly journals Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

2020 ◽  
Author(s):  
Robin N. Beaumont ◽  
Isabelle K. Mayne ◽  
Rachel M. Freathy ◽  
Caroline F. Wright
Keyword(s):  
Birth Weight ◽  
Statistical Power ◽  
Developmental Disorders ◽  
Association Studies ◽  
Later Life ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Fetal Effect ◽  
Common Genetic Variants ◽  
Causal Genes

AbstractBirth weight is an important factor in newborn and infant survival, and both low and high birth weights are associated with adverse later life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with either maternal or fetal effects on birth weight. Knowledge of the underlying causal genes and pathways is crucial to understand how these loci influence birth weight, and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme upper or lower ends of the normal distribution, and genes implicated in those syndromes may provide valuable information to help prioritise candidate genes at GWAS loci. We examined the proximity of genes implicated in developmental disorders to birth weight GWAS loci at which a fetal effect is either likely or cannot be ruled out. We used simulations to test whether those genes fall disproportionately close to the GWAS loci. We found that birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected by chance. This is the case both when the developmental disorder gene is the nearest gene to the birth weight SNP and also when examining all genes within 258kb of the SNP. This enrichment was driven by genes that cause monogenic developmental disorders with dominant modes of inheritance. We found several examples of SNPs located in the intron of one gene that mark plausible effects via different nearby genes implicated in monogenic short stature, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight loci, which has helped identify GWAS loci likely to have direct fetal effects on birth weight which could not previously be classified as fetal or maternal due to insufficient statistical power.

scholarly journals Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 772
Author(s):  
João Botelho ◽  
Vanessa Machado ◽  
José João Mendes ◽  
Paulo Mascarenhas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

scholarly journals Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

2020 ◽  
Author(s):  
Katherina C. Chua ◽  
Chenling Xiong ◽  
Carol Ho ◽  
Taisei Mushiroda ◽  
Chen Jiang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Elements ◽  
Hazard Ratio ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Sensory Peripheral Neuropathy ◽  
Genome Wide ◽  
Microtubule Targeting Agents

AbstractMicrotubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

scholarly journals Increasing Sample Diversity in Psychiatric Genetics – Introducing a new Cohort of Patients with Schizophrenia and Controls from Vietnam – Results from a Pilot Study

2021 ◽  
Author(s):  
VT Nguyen ◽  
A Braun ◽  
J Kraft ◽  
TMT Ta ◽  
GM Panagiotaropoulou ◽  
...  
Keyword(s):  
Pilot Study ◽  
Data Collection ◽  
Predictive Power ◽  
Association Studies ◽  
East Asian ◽  
Genetic Research ◽  
European Ancestry ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractObjectivesGenome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry.MethodsIn a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University’s associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: i) European, ii) East-Asian and iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis.ResultsSCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability=4.9%, p=6.83*10−8), East-Asian (R2 liability=4.5%, p=2.73*10−7) and European (R2 liability=3.8%, p = 1.79*10−6) discovery samples.DiscussionOur results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.

scholarly journals 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Mathias Gorski ◽  
Peter J. van der Most ◽  
Alexander Teumer ◽  
Audrey Y. Chu ◽  
Man Li ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Development ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
P Value ◽  
Genome Wide Association Studies ◽  
1000 Genomes ◽  
Gene Sets ◽  
Project Promise

Abstract HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

Sign in / Sign up

Export Citation Format

Share Document