Polygenic risk scores in imaging genetics: Usefulness and applications

Dima, Danai; Breen, Gerome

doi:10.1177/0269881115584470

Cited by 85 publications

(54 citation statements)

References 69 publications

(96 reference statements)

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“…On the other hand, the main advantage of the polygenic risk score method is that it provides a quantitative measure of the polygenic load of each study participant without relying on their genetic distance from an affected proband. Moreover, the PGR-BD allows modelling the cumulative effect of multiple risk-variants for BD and is known to explain a greater proportion of phenotypic variance that single riks-alleles (International Schizophrenia Consortium et al, 2009, Dima and Breen, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…In response, the polygenic risk (PGR) score method has been developed to quantify the extent to which common risk-variants may collectively capture variation in susceptibility to disease (International Schizophrenia Consortium et al, 2009). The PGR score for BD (PGR-BD) is calculated in each individual by aggregating variation across GWAS loci nominally associated with BD into a quantitative score (International Schizophrenia Consortium et al, 2009, Dima and Breen, 2015), with the current PGR-BD explaining ~ 5% of the variance to BD (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013). Two previous studies have used the polygenic risk score method to examine the cumulative impact of BD-related risk-conferring SNPs on task-related brain activation during an emotional processing (Tesli et al, 2015) and a word generation task (Whalley et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…This evidence collectively suggests that the influence of common risk-alleles on brain function may be more informative with regards to brain phenotypes related to vulnerability to BD rather than overt disease. The PGR method has a relatively higher explanatory power compared to single SNP examinations (Dima and Breen, 2015), and may be useful in identifying regions where the additive effect of common risk-alleles converges to confer vulnerability to BD.…”

Section: Introductionmentioning

confidence: 99%

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The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information

Dima

Jong

Breen

et al. 2016

NeuroImage: Clinical

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Genome-wise association studies have identified a number of common single-nucleotide polymorphisms (SNPs), each of small effect, associated with risk to bipolar disorder (BD). Several risk-conferring SNPs have been individually shown to influence regional brain activation thus linking genetic risk for BD to altered brain function. The current study examined whether the polygenic risk score method, which models the cumulative load of all known risk-conferring SNPs, may be useful in the identification of brain regions whose function may be related to the polygenic architecture of BD. We calculated the individual polygenic risk score for BD (PGR-BD) in forty-one patients with the disorder, twenty-five unaffected first-degree relatives and forty-six unrelated healthy controls using the most recent Psychiatric Genomics Consortium data. Functional magnetic resonance imaging was used to define task-related brain activation patterns in response to facial affect and working memory processing. We found significant effects of the PGR-BD score on task-related activation irrespective of diagnostic group. There was a negative association between the PGR-BD score and activation in the visual association cortex during facial affect processing. In contrast, the PGR-BD score was associated with failure to deactivate the ventromedial prefrontal region of the default mode network during working memory processing. These results are consistent with the threshold-liability model of BD, and demonstrate the usefulness of the PGR-BD score in identifying brain functional alternations associated with vulnerability to BD. Additionally, our findings suggest that the polygenic architecture of BD is not regionally confined but impacts on the task-dependent recruitment of multiple brain regions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information

Dima

Jong

Breen

et al. 2016

NeuroImage: Clinical

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“…27,28 This pattern implies that restricting analyses to a small number of risk loci provides a weak signal of underlying genetic risk that is improved by aggregating effects across many loci. Our results might further explain discrepancies reported across exploratory GWAS studies of AD markers.…”

Section: (Pgrs) Discrimination Between Patients With Alzheimer Diseasmentioning

confidence: 99%

Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Sperling²,

et al. 2016

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Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies. Methods:We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and b-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years).Results: Within participants without dementia, elevated PGRS was associated with worse memory (p The asymptomatic stage of Alzheimer disease (AD) is thought to last over a decade, during which the pathophysiologic processes are under way in the absence of clinical symptoms.1 Given that current clinical trials are testing whether antiamyloid therapies slow cognitive decline among clinically normal individuals at risk for AD dementia, 2,3 it is critical to understand the influence of risk factors before overt symptoms of dementia are present. Coinvestigators are listed at Neurology.org.Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at

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“…A polygenic risk score (PRS) 33 is an approximate measure of an individual’s common variant genetic propensity for a given disorder and, at a population level shows some predictive power 34 for case-control status. PRS approaches provide several potential routes to drug development, including identification of genetically associated endophenotypes and biomarkers.…”

Section: Precision Medicine For Psychiatry and Polygenic Risk Scoresmentioning

confidence: 99%

Translating genome-wide association findings into new therapeutics for psychiatry

et al. 2016

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Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to (cumulatively) >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. These approaches complement the other main aim of GWAS studies on risk prediction approaches for improving detection, differential diagnosis, and clinical trial design. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC3 findings into new therapeutics.

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Polygenic risk scores in imaging genetics: Usefulness and applications

Cited by 85 publications

References 69 publications

The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information

The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information

Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Translating genome-wide association findings into new therapeutics for psychiatry

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