Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Palmer, Duncan S.; Howrigan, Daniel P.; Chapman, Sinéad B.; Adolfsson, Rolf; Bass, Nick; Blackwood, Douglas; Boks, Marco P.; Chen, Chia Yen; Churchhouse, Claire; Corvin, Aiden; Craddock, Nicholas; Curtis, David; Florio, Arianna Di; Dickerson, Faith; Freimer, Nelson A.; Goes, Fernando S.; Jia, Xiaoming; Jones, Ian; Jones, L. A.; Jönsson, Lina; Kahn, René S.; Landén, Mikael; Locke, Adam E.; McIntosh, Andrew M.; McQuillin, Andrew; Morris, Derek W.; O'Donovan, Michael Conlon; Ophoff, Roel A.; Owen, Michael John; Pedersen, Nancy L.; Posthuma, Daniëlle; Reif, Andreas; Risch, Neil; Schaefer, Catherine; Scott, Laura J.; Singh, Tarjinder; Smoller, Jordan W; Solomonson, Matthew; Clair, David St; Stahl, Eli A.; Vreeker, Annabel; Walters, James; Wang, Weiqing; Watts, Nicholas A.; Yolken, Robert H.; Zandi, Peter P.; Neale, Benjamin M.

doi:10.1038/s41588-022-01034-x

Cited by 110 publications

(88 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A consistent observation in exome-based analyses of neuropsychiatric disorders is an enrichment of significant associations in constrained genes 6,7 . Indeed, in the top quintile of constrained genes, burden heritability is 15.9x (SE = 1.7x) enriched for schizophrenia and 4.4x (SE = 1.2x) enriched for bipolar disorder (Figure 6B).…”

Section: Burden Heritability Of Schizophrenia and Bipolar Disordermentioning

confidence: 65%

“…Burden heritability is also more strongly concentrated in constrained genes (median enrichment: 4.5x vs. 2.1x for common variants), indicating that negative selection affects common- and rare-variant architecture differently. Finally, we find that burden heritability for schizophrenia and bipolar disorder 6,7 is especially high (3.8% and 3.6%). Our results show that there are a tractable number of large-effect genes to discover by studying rare variants, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.…”

mentioning

confidence: 73%

See 1 more Smart Citation

Polygenic architecture of rare coding variation across 400,000 exomes

Weiner

Nadig

Jagadeesh

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have discovered thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes. However, rare-variant genetic architecture is not well characterized, and the relationship between common- and rare- variant architecture is unclear. Here, we quantify the heritability explained by gene-wise burden of rare coding variants and compare the genetic architecture of common and rare variation across 22 common traits and diseases in 400,000 UK Biobank exomes. Rare coding variants (AF = 1e-6 - 1e-3) explain 1.3% (SE = 0.03%) of phenotypic variance on average - much less than common variants - and most burden heritability is explained by ultra-rare loss-of-function variants (AF = 1e-6 - 1e-5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in a limited number of significant genes (median: 6 genes explaining 19% of h2), while common-variant heritability is much more polygenic. Burden heritability is also more strongly concentrated in constrained genes (median enrichment: 4.5x vs. 2.1x for common variants), indicating that negative selection affects common- and rare-variant architecture differently. Finally, we find that burden heritability for schizophrenia and bipolar disorder is especially high (3.8% and 3.6%). Our results show that there are a tractable number of large-effect genes to discover by studying rare variants, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.

show abstract

Section: Burden Heritability Of Schizophrenia and Bipolar Disordermentioning

confidence: 65%

mentioning

confidence: 73%

Polygenic architecture of rare coding variation across 400,000 exomes

Weiner

Nadig

Jagadeesh

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Analysis conducted by Andlauer et al [27] on BIP multiplex families have shown that unlike familial SCZ cases studied here, familial BIP cases have a significantly higher BIP PRS compared to ancestry matched, sporadic cases. These results, in addition to sparse evidence for the involvement of rare risk variation in the genetic architecture of BIP [22], demonstrates the importance of common risk variation in familial BIP, whereas whole exome sequencing studies of SCZ in both family and case-control samples have demonstrated that in addition to common variation, rare variation also plays an important role in the genetic architecture of SCZ [21,[51][52][53].…”

Section: Discussionmentioning

confidence: 91%

“…Another explanation is that the increased recurrence risk in multiplex families may be attributable to segregation of rarer, higher risk variation, identifiable through exome or whole-genome sequencing likely in combination with common risk variation. Sequencing studies suggest that rare, deleterious variation in the genome is involved in the genetic etiology of SCZ and other psychiatric disorders [15][16][17][18][19][20][21][22], but the extent to which rare variation contributes to SCZ risk in multiplex families is currently unknown. A third hypothesis, not addressed here, is that familial cases may have increased exposure to environmental risks unique to the families that may explain the higher recurrence risk in multiplex families.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families

Ahangari

Gentry

Morris³

et al. 2022

Transl Psychiatry

Self Cite

View full text Add to dashboard Cite

Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia genome-wide association study data (N = 156,509) to construct polygenic risk scores (PRS) in 1005 individuals from 257 multiplex schizophrenia families, 2114 ancestry-matched sporadic cases, and 2205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.90, FH+ cases p = 0.88, FH− cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.

show abstract

“…We also downloaded rare segregating variants in cases and controls, available publicly for epilepsy, autism, schizophrenia, and bipolar disorder (10,12,14,17). Note that each study defined rare variants based on their own criteria: for example, the autism study designates rare variants as those with “allele frequency ≤ 0.1% in our dataset and non-psychiatric subsets of reference databases” (14).…”

Section: Methodsmentioning

confidence: 99%

Relating pathogenic loss-of function mutations in humans to their evolutionary fitness costs

Agarwal

Fuller

Myers

et al. 2022

Preprint

View full text Add to dashboard Cite

Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in "mutation intolerant" genes. We show how such observations can be interpreted in light of a model of mutation-selection balance, and use the model to relate the pathogenic consequences of LOF mutations at present-day to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,322 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We then compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, such highly deleterious mutations are typically only a couple of generations old when sampled in the population. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.

show abstract

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Abstract: B. M. (2022). Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.

Cited by 110 publications

References 56 publications

Polygenic architecture of rare coding variation across 400,000 exomes

Polygenic architecture of rare coding variation across 400,000 exomes

Evaluating the role of common risk variation in the recurrence risk of schizophrenia in multiplex schizophrenia families

Relating pathogenic loss-of function mutations in humans to their evolutionary fitness costs

Contact Info

Product

Resources

About