Review of statistical methodologies for the detection of parent-of-origin effects in family trio genome-wide association data with binary disease traits

Connolly, Siobhan; Heron, Elizabeth A.

doi:10.1093/bib/bbu017

Cited by 32 publications

(39 citation statements)

References 60 publications

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“…Following an extensive review of the parent-of-origin methodology, described elsewhere, 22 we used the EMIM 23,24 approach for our analyses. EMIM is a multinomial model that directly maximises the multinomial likelihood to detect parent-of-origin effects and can incorporate missing data (Supplementary Information for further details).…”

Section: Statistical Modelmentioning

confidence: 99%

“…We did not include mother/offspring interactions in our model as the inclusion of mother/offspring interaction parameters reduces the power of the model substantially, as is to be expected. 22 Instead mother/offspring interaction effects were investigated subsequent to a SNP being identified as having an offspring effect and a maternal genetic effect. A multiplicative model was assumed for offspring and maternal genotype parameters.…”

Section: Statistical Modelmentioning

confidence: 99%

“…Power to detect parent-of-origin effects can be limited 22 and the current genome-wide significance threshold guidelines are known to be very stringent. 25,26,30 These genome-wide significance levels are suggested for all sample sizes (and MAFs) and hence do not take into account the power at individual SNPs.…”

Section: Bayesian Noteworthy Thresholdmentioning

confidence: 99%

“…18,19 Our analysis approach differs in that we investigated both imprinting and maternal genetic effects simultaneously as maternal genetic effects are known to mimic imprinting and vice versa. 21,22 We also included offspring genetic effects (associations) in our model to enable us to identify an imprinting effect associated with ASD. These parentof-origin analyses were investigated using estimation of maternal, imprinting and interaction effects using multinomial modelling (EMIM), 23,24 which in comparison with other tests has been shown to be the most suitable in terms of power and type I errors for this type of data.…”

Section: Introductionmentioning

confidence: 99%

“…These parentof-origin analyses were investigated using estimation of maternal, imprinting and interaction effects using multinomial modelling (EMIM), 23,24 which in comparison with other tests has been shown to be the most suitable in terms of power and type I errors for this type of data. 22 We also adapted a Bayesian method 25 to determine an appropriate noteworthy threshold at each locus (taking into account sample size, minor allele frequency (MAF) and prior knowledge) instead of using the genome-wide significance levels, which are known to be stringent. 26 …”

Section: Introductionmentioning

confidence: 99%

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A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3

et al. 2016

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Autism spectrum disorder (ASD) is known to be a heritable neurodevelopmental disorder affecting more than 1% of the population but in the majority of ASD cases, the genetic cause has not been identified. Parent-of-origin effects have been highlighted as an important mechanism in the pathology of neurodevelopmental disorders such as Prader-Willi and Angelman syndrome, with individuals with these syndromes often exhibiting ASD symptoms. Consequently, systematic investigation of these effects in ASD is clearly an important line of investigation in elucidating the underlying genetic mechanisms. Using estimation of maternal, imprinting and interaction effects using multinomial modelling (EMIM), we simultaneously investigated imprinting, maternal genetic effects and associations in the Autism Genome Project and Simons Simplex Consortium genome-wide association data sets. To avoid using the overly stringent genome-wide association study significance level, we used a Bayesian threshold that takes into account the sample size, allele frequency and any available prior knowledge. Between the two data sets, we identified a total of 18 imprinting effects and 68 maternal genetic effects that met this Bayesian threshold criteria, but none met the threshold in both data sets. We identified imprinting and maternal genetic effects for regions that have previously shown evidence for parent-of-origin effects in ASD. Together with these findings, we have identified maternal genetic effects not previously identified in ASD at a locus in SHANK3 on chromosome 22 and a locus in WBSCR17 on chromosome 7 (associated with Williams syndrome). Both genes have previously been associated with ASD. INTRODUCTIONAutism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder characterised by patterns of repetitive behaviours and deficits in language and social behaviour. ASD is known to be heritable, with earlier heritability estimates ranging from 0.85 to 0.92 1 to a more current heritability estimate of 0.524, 2 with most of this believed to be due to common rather than rare variation. 2 Gaugler et al 2 also estimated that 41% of the risk for ASD is due to environmental factors, which include prenatal, perinatal and postnatal environmental factors. Several genome-wide association studies (GWASs) have been performed on common variants in ASD using family studies, but the most significant results from these studies show modest effect size 3-5 and therefore, have low power to replicate. 4 Despite growing evidence from investigations of rare and de novo structural and sequence variation in ASD, 6 the aetiology of the majority of ASD cases remains unexplained, suggesting that there are complex genetic mechanisms underlying the disorder. There is also evidence to suggest that there is a complex relationship between these underlying genetic factors and environmental factors. 7 Broadly speaking, parent-of-origin effects consist of genetic effects on the phenotype of an offspring that are dependent on the parental origin of the...

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Section: Statistical Modelmentioning

confidence: 99%

Section: Statistical Modelmentioning

confidence: 99%

Section: Bayesian Noteworthy Thresholdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3

et al. 2016

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A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

Nembhard

Tang

et al. 2018

American J of Med Genetics Pt A

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The association between conotruncal heart defects (CTHDs) and maternal genetic and environmental exposures is well studied. However, little is known about paternal genetic or environmental exposures and risk of CTHDs. We assessed the effect of paternal genetic variants in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs in offspring. We utilized National Birth Defects Prevention Study data to conduct a family-based case only study using 616 live-born infants with CTHDs, born October 1997-August 2008. Maternal, paternal and infant DNA was genotyped using an Illumina® Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR) and 95% confidence intervals (CI) from log-linear models determined parent of origin effects for 921 SNPs in 60 candidate genes involved in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs. The risk of CTHD among children who inherited a paternally derived copy of the A allele on GLRX (rs17085159) or the T allele of GLRX (rs12109442) was 0.23 (95%CI: 0.12, 0.42; p = 1.09 × 10 ) and 0.27 (95%CI: 0.14, 0.50; p = 2.06 × 10 ) times the risk among children who inherited a maternal copy of the same allele. The paternally inherited copy of the GSR (rs7818511) A allele had a 0.31 (95%CI: 0.18, 0.53; p = 9.94 × 10 ] risk of CTHD compared to children with the maternal copy of the same allele. The risk of CTHD is less influenced by variants in paternal genes involved in the folate, homocysteine, or transsulfuration pathways than variants in maternal genes in those pathways.

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Genomic Imprinting As a Window into Human Language Evolution

2019

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Humans spend large portions of their time and energy talking to one another, yet it remains unclear whether this activity is primarily selfish or altruistic. Here, it is shown how parent‐of‐origin specific gene expression—or “genomic imprinting”—may provide an answer to this question. First, it is shown why, regarding language, only altruistic or selfish scenarios are expected. Second, it is pointed out that an individual's maternal‐origin and paternal‐origin genes may have different evolutionary interests regarding investment into language, and that this intragenomic conflict may drive genomic imprinting which—as the direction of imprint depends upon whether investment into language is relatively selfish or altruistic—may be used to discriminate between these two possibilities. Third, predictions concerning the impact of various mutations and epimutations at imprinted loci on language pathologies are derived. In doing so, a framework is developed that highlights avenues for using intragenomic conflicts to investigate the evolutionary drivers of language.

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Review of statistical methodologies for the detection of parent-of-origin effects in family trio genome-wide association data with binary disease traits

Cited by 32 publications

References 60 publications

A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3

A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3

A parent‐of‐origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

Genomic Imprinting As a Window into Human Language Evolution

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