Dataset Information

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

ABSTRACT: There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

SUBMITTER: Ganna A

PROVIDER: S-EPMC5992130 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

Ganna Andrea A Satterstrom F Kyle FK Zekavat Seyedeh M SM Das Indraniel I Kurki Mitja I MI Churchhouse Claire C Alfoldi Jessica J Martin Alicia R AR Havulinna Aki S AS Byrnes Andrea A Thompson Wesley K WK Nielsen Philip R PR Karczewski Konrad J KJ Saarentaus Elmo E Rivas Manuel A MA Gupta Namrata N Pietiläinen Olli O Emdin Connor A CA Lescai Francesco F Bybjerg-Grauholm Jonas J Flannick Jason J Mercader Josep M JM Udler Miriam M Laakso Markku M Salomaa Veikko V Hultman Christina C Ripatti Samuli S Hämäläinen Eija E Moilanen Jukka S JS Körkkö Jarmo J Kuismin Outi O Nordentoft Merete M Hougaard David M DM Mors Ole O Werge Thomas T Mortensen Preben Bo PB MacArthur Daniel D Daly Mark J MJ Sullivan Patrick F PF Locke Adam E AE Palotie Aarno A Børglum Anders D AD Kathiresan Sekar S Neale Benjamin M BM

American journal of human genetics 20180531 6

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association wi ...[more]

PMID: 29861106

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Project description:BackgroundThe Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV).MethodsSNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes.ResultsOf 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy.LimitationsThe cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification.ConclusionsIn this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD.

Dataset Information

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

Publications

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

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