Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Ganna, Andrea; Satterstrom, Kyle; Zekavat, Seyedeh M.; Das, Indraniel; Kurki, Mitja; Churchhouse, Claire; Alföldi, Jessica; Martin, Alicia R.; Havulinna, Aki S.; Byrnes, Andrea; Thompson, Wesley K.; Nielsen, Philip; Karczewski, Konrad J.; Saarentaus, Elmo; Rivas, Manuel A.; Gupta, Namrata; Pietiläinen, Olli; Emdin, Connor A.; Lescai, Francesco; Bybjerg‐Grauholm, Jonas; Flannick, Jason; Mercader, Josep M.; Udler, Miriam S.; Laakso, Markku; Salomaa, Veikko; Hultman, Christina M.; Ripatti, Samuli; Hämäläinen, Eija; Moilanen, Jukka S.; Körkkö, Jarmo; Kuismin, Outi; Nordentoft, Merete; Hougaard, David M.; Mors, Ole; Werge, Thomas; Mortensen, Preben Bo; MacArthur, Daniel G.; Daly, Mark J.; Sullivan, Patrick F.; Locke, Adam E.; Palotie, Aarno; Børglum, Anders; Kathiresan, Sekar; Neale, Benjamin M.

doi:10.1101/148247

Cited by 35 publications

(47 citation statements)

References 28 publications

(16 reference statements)

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“…Multifactorial traits such as personality and educational attainment are thought to have complex genetic aetiologies, consisting of interplay between common and rare variation. Recent exome sequencing work has demonstrated rare coding variant effects on many psychiatric traits (that are closely related to neuroticism; (Ganna et al 2018)).…”

Section: Discussionmentioning

confidence: 99%

Familial influences on Neuroticism and Education in the UK Biobank

Cheesman

Coleman

Rayner

et al. 2019

Preprint

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Genome-wide studies often exclude family members, even though they are a valuable source of information. We identified parent-offspring pairs, siblings and couples in the UK Biobank and implemented a family-based DNA-derived heritability method to capture additional genetic effects and multiple sources of environmental influence on neuroticism and years of education. Compared to estimates from unrelated individuals, heritability increased from 10% to 27% and from 19% to 57% for neuroticism and education respectively by including family-based genetic effects. We detected no family environmental influences on neuroticism, but years of education was substantially influenced by couple similarity (38%). Overall, our genetic and environmental estimates closely replicate previous findings from an independent sample, but more research is required to dissect contributions to the additional heritability, particularly rare and structural genetic effects and residual environmental confounding. The latter is especially relevant for years of education, a highly socially-contingent variable, for which our heritability estimate is at the upper end of twin estimates in the literature. Family-based genetic effects narrow the gap between twin and DNA-based heritability methods, and could be harnessed to improve polygenic prediction.

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Section: Discussionmentioning

confidence: 99%

Familial influences on Neuroticism and Education in the UK Biobank

Cheesman

Coleman

Rayner

et al. 2019

Preprint

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“…Accumulating evidence suggests that common and rare variation act additively to influence complex traits [59,60]. Here, we report a model to leverage information from both rare and common variants to understand the biological basis of reproduction, a multifactorial phenotype.…”

Section: Discussionmentioning

confidence: 99%

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Männik

Arbogast

Lepamets

et al. 2019

Preprint

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Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

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“…Supporting this approach, a recent analysis noted that the strength of disease association for a nonsynonymous variant increased with the greater number of deleterious predictions in silico. 63 Fourth, inherent to the prioritization criteria of rarity, deleteriousness and segregation, the NSD-S and disruptive variant set presented above would explain only a part of an individual's liability to disease. The results of this analysis represent the shared Using WES data in multiplex families with SMI, we find evidence that suggests intersections in the molecular pathways leading to the expression of polygenic SMI and Mendelian neuropsychiatric syndromes.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

Ganesh

Pallikonda

Nadella

et al. 2018

Psychiatry Clin Neurosci

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Aim Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome‐wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next‐generation sequencing may add to the understanding of the genetic architecture of SMI. Methods We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole‐exome sequencing. Prioritized variants were selected by a three‐step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool. Results We identified 42 rare, non‐synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome. Conclusion Next‐generation sequencing approaches in family‐based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

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Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Cited by 35 publications

References 28 publications

Familial influences on Neuroticism and Education in the UK Biobank

Familial influences on Neuroticism and Education in the UK Biobank

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

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