Dataset Information

Health and population effects of rare gene knockouts in adult humans with related parents.

ABSTRACT: Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

SUBMITTER: Narasimhan VM

PROVIDER: S-EPMC4985238 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Health and population effects of rare gene knockouts in adult humans with related parents.

Narasimhan Vagheesh M VM Hunt Karen A KA Mason Dan D Baker Christopher L CL Karczewski Konrad J KJ Karczewski Konrad J KJ Barnes Michael R MR Barnett Anthony H AH Bates Chris C Bellary Srikanth S Bockett Nicholas A NA Giorda Kristina K Griffiths Christopher J CJ Hemingway Harry H Jia Zhilong Z Kelly M Ann MA Khawaja Hajrah A HA Lek Monkol M McCarthy Shane S McEachan Rosie R O'Donnell-Luria Anne A Paigen Kenneth K Parisinos Constantinos A CA Sheridan Eamonn E Southgate Laura L Tee Louise L Thomas Mark M Xue Yali Y Schnall-Levin Michael M Petkov Petko M PM Tyler-Smith Chris C Maher Eamonn R ER Trembath Richard C RC MacArthur Daniel G DG Wright John J Durbin Richard R van Heel David A DA

Science (New York, N.Y.) 20160303 6284

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were link ...[more]

PMID: 26940866

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Project description:OBJECTIVES:To describe the distribution of health-related quality of life (HRQL) in a national sample of Australian children aged 11-12 years and their parents, and examine associations within parent-child dyads. DESIGN:The Child Health CheckPoint, a population-based cross-sectional study nested between waves 6 and 7 of the Longitudinal Study of Australian Children (LSAC). SETTING:Assessment centres in seven Australian cities and eight regional towns, or home visit; February 2015 to March 2016. PARTICIPANTS:Of all participating CheckPoint families (n=1874), 1853 children (49.0% girls) and 1863 parents (87.7% mothers) with HRQL data were included (1786 pairs). OUTCOME MEASURES:HRQL was self-reported using preference-based (Child Health Utility 9Dimension, CHU9D) and non-preference-based (Pediatric Quality of Life, PedsQL V.4.0) measures for children and preference-based measures for parents (CHU9D; Assessment of Quality of Life 8 Dimension, AQoL-8D). Utility scores from preference-based measures were calculated using existing Australian algorithms to present a score on a 0-1 scale, where 1 represents full health. Parent-child concordance was assessed using Pearson's correlation coefficients and adjusted linear regression models. Survey weights and methods were applied to account for LSAC's complex sample design, stratification and clustering within postcodes. RESULTS:Children's means and SD were 0.81 (SD 0.16) for CHU9D and 78.3 (SD 13.03) for PedsQL. In adults, mean HRQL for AQoL-8D and CHU9D were 0.78 (SD 0.16) and 0.89 (SD 0.10), respectively. Mean HRQL was similar for boys and girls, but slightly higher for fathers than mothers. The Pearson correlation coefficient for parent-child CHU9D values was 0.13 (95% CI 0.09 to 0.18). Percentiles and concordance are presented for both samples for males and females separately and together. CONCLUSIONS:We provide Australian paediatric population values for HRQL measures, and the first national CHU9D values for mid-life adults. At age 11-12 years in this relatively healthy sample, parent-child concordance in HRQL was small.

Dataset Information

Health and population effects of rare gene knockouts in adult humans with related parents.

Publications

Health and population effects of rare gene knockouts in adult humans with related parents.

Similar Datasets

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