Explaining the missing heritability of psychiatric disorders

Williams, Nigel

doi:10.1002/wps.20870

Cited by 25 publications

(16 citation statements)

References 9 publications

(15 reference statements)

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“…1d ). With partitioned LD Score regression (LDSC) we used the associations of all SNPs, because much of the of polygenic traits lies in SNPs that do not reach genome-wide significance 10 . An enrichment of after Bonferroni correction was observed in four functional genomic categories, specifically within regions with three distinct types of chromatin modifications (Supplementary Data 1 ).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

et al. 2022

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Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations study for cerebellar volume was performed in a discovery sample of 27,486 individuals from UK Biobank, resulting in 30 genome-wide significant loci and a SNP heritability of 39.82%. We pinpoint the likely causal variants and those that have effects on amino acid sequence or cerebellar gene-expression. Additionally, 85 genome-wide significant genes were detected and tested for convergence onto biological pathways, cerebellar cell types, human evolutionary genes or developmental stages. Local genetic correlations between cerebellar volume and neurodevelopmental and neurodegenerative disorders reveal shared loci with Parkinson’s disease, Alzheimer’s disease and schizophrenia. These results provide insights into the heritable mechanisms that contribute to developing a brain structure important for cognitive functioning and mental health.

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Section: Resultsmentioning

confidence: 99%

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

et al. 2022

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“…Compared with the average twin heritability of human traits of 49% (Polderman et al, 2015), SNP heritability estimates are much lower. Twin heritability estimates may be inflated because of non-captured shared environmental confounding factors and SNP heritability may be deflated by not accounting for rare and small effects (Manolio et al, 2009;Owen & Williams, 2021). In the present study, we used both types of heritability estimates: twin heritability as the trait variance that can be explained by quantitative genetics and SNP heritability as the trait variance that can be explained by molecular genetics approaches.…”

Section: Genetic Confounding In Peer Bullying Research: Causal Claims...mentioning

confidence: 99%

Genetic Confounding in Bullying Research: Causal Claims Revisited

Vrijen¹,

Nolte²,

Oldehinkel³

et al. 2022

Preprint

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Bullying research has shown repeatedly that victims of bullying have an increased risk for later internalizing problems and bullies have an increased risk for later externalizing problems. Bullying involvement is often, either explicitly or implicitly, presented as part of a causal mechanism for maladjustment. However, genetic vulnerability may confound the reported associations. This study examined to what extent genetic vulnerability can account for the reported associations between bullying involvement (age 11-14) and later internalizing and externalizing problems (age 16), using data from the TRacking Adolescents' Individual Lives Survey (n = 1604). Because polygenic scores capture only a fraction of the total genetic effect, they were extrapolated to the size of SNP and twin heritability estimates to examine genetic confounding while controlling for (hypothetic) polygenic scores that capture the genetic effect fully. Genetic vulnerability for internalizing and externalizing problems confounded, respectively, the association between bullying victimization and later internalizing problems, and the association between bullying perpetration and later externalizing problems. This study showcases a method that can be broadly used to assess the magnitude of genetic confounding. Caution is warranted in interpreting particularly the less straightforward extrapolations of polygenic scores to the size of twin heritability estimates.

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“…All major psychiatric conditions have a heritable component [8], with the heritability of many being quite high; estimates for schizophrenia, autism spectrum disorder (ASD) and bipolar disorder are some of the highest (0.81, 0.80 and 0.75, respectively) [5]. However, the origin of much of this heritability remains unclear [12 ▪ ].…”

Section: The Current State Of Psychiatric Geneticsmentioning

confidence: 99%

“…Many academics in the late 18th and 19th centuries understood there was a hereditable component to 'insanity', viewing family history as the single most important factor in development of disease [9 & ]. Despite a lack of knowledge of genetic inheritance -let alone epigenetics -many also noted that hereditable factors only predisposed an individual to psychiatric illness, with one or more environmental factors (or 'trigger' events) needed for psychiatric illness to manifest [9 ]. Today, there is considerable evidence that multiple genetic and environmental factors contribute to the development of psychiatric conditions [7 && ,8,10 && ,11 && ].…”

Section: The Current State Of Psychiatric Geneticsmentioning

confidence: 99%

Genetic testing for psychiatric illness in children: ethical issues

Lynch

Vears

2022

Current Opinion in Pediatrics

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Purpose of reviewGenetic and genomic technologies are showing great potential in the field of psychiatry. Genetic testing for psychiatric conditions poses a range of ethical challenges, many of which are likely to be exacerbated for paediatric populations. As a large proportion of psychiatric conditions present in late adolescence and early adulthood, testing in childhood may be considered in some circumstances. Synthesis of issues specific to psychiatric genetic testing in paediatric populations has been limited.Recent findingsBalancing the autonomy of the child and parents requires consideration and judging capacity may be complicated by the presence of psychiatric illness in the child and their family. Health professionals’ limited understanding of psychiatric genetics may inhibit delivery of effective psychiatric care. Risk of stigma and discrimination associated with genetic diagnosis and psychiatric illness is compounded for children, who inherently cannot make their own decisions and for whom the impact of a genetic diagnosis is likely to be longest lasting.SummaryAlthough the current evidence base suggests genetic testing may not be appropriate for clinical use in psychiatric populations right now, when it is, appropriate pre-test counselling and informed decision making will be essential to support and protect children's developing and future autonomy.

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Explaining the missing heritability of psychiatric disorders

Cited by 25 publications

References 9 publications

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

Genome-wide association study of cerebellar volume provides insights into heritable mechanisms underlying brain development and mental health

Genetic Confounding in Bullying Research: Causal Claims Revisited

Genetic testing for psychiatric illness in children: ethical issues

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