IDEAS home Printed from https://ideas.repec.org/a/plo/pbio00/2002458.html
   My bibliography  Save this article

Identifying genetic variants that affect viability in large cohorts

Author

Listed:
  • Hakhamanesh Mostafavi
  • Tomaz Berisa
  • Felix R Day
  • John R B Perry
  • Molly Przeworski
  • Joseph K Pickrell

Abstract

A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10−6 for fathers and P~2.0 × 10−3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10−3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.Author summary: Our global understanding of adaptation in humans is limited to indirect statistical inferences from patterns of genetic variation, which are sensitive to past selection pressures. We introduced a method that allowed us to directly observe ongoing selection in humans by identifying genetic variants that affect survival to a given age (i.e., viability selection). We applied our approach to the GERA cohort and parents of the UK Biobank participants. We found viability effects of variants near the APOE and CHRNA3 genes, which are associated with the risk of Alzheimer disease and smoking behavior, respectively. We also tested for the joint effect of sets of genetic variants that influence quantitative traits. We uncovered an association between longer life span and genetic variants that delay puberty timing and age at first birth. We also detected detrimental effects of higher genetically predicted cholesterol levels, body mass index, risk of coronary artery disease (CAD), and risk of asthma on survival. Some of the observed effects differ between males and females, most notably those at the CHRNA3 gene and variants associated with risk of CAD and cholesterol levels. Beyond this application, our analysis shows how large biomedical data sets can be used to study natural selection in humans.

Suggested Citation

  • Hakhamanesh Mostafavi & Tomaz Berisa & Felix R Day & John R B Perry & Molly Przeworski & Joseph K Pickrell, 2017. "Identifying genetic variants that affect viability in large cohorts," PLOS Biology, Public Library of Science, vol. 15(9), pages 1-29, September.
  • Handle: RePEc:plo:pbio00:2002458
    DOI: 10.1371/journal.pbio.2002458
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2002458
    Download Restriction: no

    File URL: https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.2002458&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pbio.2002458?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Peter K. Joshi & Krista Fischer & Katharina E. Schraut & Harry Campbell & Tõnu Esko & James F. Wilson, 2016. "Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan," Nature Communications, Nature, vol. 7(1), pages 1-7, September.
    2. Felix R. Day & Brendan Bulik-Sullivan & David A. Hinds & Hilary K. Finucane & Joanne M. Murabito & Joyce Y. Tung & Ken K. Ong & John R.B. Perry, 2015. "Shared genetic aetiology of puberty timing between sexes and with health-related outcomes," Nature Communications, Nature, vol. 6(1), pages 1-6, December.
    3. Pleuni S Pennings & Joachim Hermisson, 2006. "Soft Sweeps III: The Signature of Positive Selection from Recurrent Mutation," PLOS Genetics, Public Library of Science, vol. 2(12), pages 1-15, December.
    4. Bryan N Howie & Peter Donnelly & Jonathan Marchini, 2009. "A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies," PLOS Genetics, Public Library of Science, vol. 5(6), pages 1-15, June.
    5. Jeremy J Berg & Graham Coop, 2014. "A Population Genetic Signal of Polygenic Adaptation," PLOS Genetics, Public Library of Science, vol. 10(8), pages 1-25, August.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Pietro Biroli & Titus Galama & Stephanie von Hinke & Hans van Kippersluis & Cornelius Rietveld & Kevin Thom, 2022. "The Economics and Econometrics of Gene-Environment Interplay," Tinbergen Institute Discussion Papers 22-019/V, Tinbergen Institute.
    2. Frank J Wolters & Qiong Yang & Mary L Biggs & Johanna Jakobsdottir & Shuo Li & Daniel S Evans & Joshua C Bis & Tamara B Harris & Ramachandran S Vasan & Nuno R Zilhao & Mohsen Ghanbari & M Arfan Ikram , 2019. "The impact of APOE genotype on survival: Results of 38,537 participants from six population-based cohorts (E2-CHARGE)," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-13, July.
    3. Pereira, Rita & Biroli, Pietro & von hinke, stephanie & Van Kippersluis, Hans & Galama, Titus & Rietveld, Niels & Thom, Kevin, 2022. "Gene-Environment Interplay in the Social Sciences," OSF Preprints d96z3_v1, Center for Open Science.
    4. Rita Dias Pereira & Pietro Biroli & Titus Galama & Stephanie von Hinke & Hans van Kippersluis & Cornelius A. Rietveld & Kevin Thom, 2022. "Gene-Environment Interplay in the Social Sciences," Papers 2203.02198, arXiv.org, revised Aug 2022.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Chuan Gao & Nan Wang & Xiuqing Guo & Julie T Ziegler & Kent D Taylor & Anny H Xiang & Yang Hai & Steven J Kridel & Jerry L Nadler & Fouad Kandeel & Leslie J Raffel & Yii-Der I Chen & Jill M Norris & J, 2015. "A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS)," PLOS ONE, Public Library of Science, vol. 10(11), pages 1-17, November.
    2. Rakesh Chettier & Lesa Nelson & James W Ogilvie & Hans M Albertsen & Kenneth Ward, 2015. "Haplotypes at LBX1 Have Distinct Inheritance Patterns with Opposite Effects in Adolescent Idiopathic Scoliosis," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-11, February.
    3. Michel S. Naslavsky & Marilia O. Scliar & Guilherme L. Yamamoto & Jaqueline Yu Ting Wang & Stepanka Zverinova & Tatiana Karp & Kelly Nunes & José Ricardo Magliocco Ceroni & Diego Lima Carvalho & Carlo, 2022. "Whole-genome sequencing of 1,171 elderly admixed individuals from Brazil," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Carl Nettelblad, 2013. "Breakdown of Methods for Phasing and Imputation in the Presence of Double Genotype Sharing," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-5, March.
    5. Lindsay Fernández-Rhodes & Jennifer R Malinowski & Yujie Wang & Ran Tao & Nathan Pankratz & Janina M Jeff & Sachiko Yoneyama & Cara L Carty & V Wendy Setiawan & Loic Le Marchand & Christopher Haiman &, 2018. "The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic ," PLOS ONE, Public Library of Science, vol. 13(7), pages 1-21, July.
    6. Viinikainen, Jutta & Bryson, Alex & Böckerman, Petri & Kari, Jaana T. & Lehtimäki, Terho & Raitakari, Olli & Viikari, Jorma & Pehkonen, Jaakko, 2022. "Does better education mitigate risky health behavior? A mendelian randomization study," Economics & Human Biology, Elsevier, vol. 46(C).
    7. Morten Dybdahl Krebs & Gonçalo Espregueira Themudo & Michael Eriksen Benros & Ole Mors & Anders D. Børglum & David Hougaard & Preben Bo Mortensen & Merete Nordentoft & Michael J. Gandal & Chun Chieh F, 2021. "Associations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    8. Mette K Andersen & Emil Jørsboe & Line Skotte & Kristian Hanghøj & Camilla H Sandholt & Ida Moltke & Niels Grarup & Timo Kern & Yuvaraj Mahendran & Bolette Søborg & Peter Bjerregaard & Christina V L L, 2020. "The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders," PLOS Genetics, Public Library of Science, vol. 16(1), pages 1-17, January.
    9. Hans M Albertsen & Rakesh Chettier & Pamela Farrington & Kenneth Ward, 2013. "Genome-Wide Association Study Link Novel Loci to Endometriosis," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-8, March.
    10. Faheem Mitha & Herodotos Herodotou & Nedyalko Borisov & Chen Jiang & Josh Yoder & Kouros Owzar, 2011. "SNPpy - Database Management for SNP Data from Genome Wide Association Studies," PLOS ONE, Public Library of Science, vol. 6(10), pages 1-8, October.
    11. Qingqin S Li & Antonio R Parrado & Mahesh N Samtani & Vaibhav A Narayan & Alzheimer’s Disease Neuroimaging Initiative, 2015. "Variations in the FRA10AC1 Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Aβ1-42 Level," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-17, August.
    12. Peng Chen & Rick Twee-Hee Ong & Wan-Ting Tay & Xueling Sim & Mohammad Ali & Haiyan Xu & Chen Suo & Jianjun Liu & Kee-Seng Chia & Eranga Vithana & Terri L Young & Tin Aung & Wei-Yen Lim & Chiea-Chuen K, 2013. "A Study Assessing the Association of Glycated Hemoglobin A1C (HbA1C) Associated Variants with HbA1C, Chronic Kidney Disease and Diabetic Retinopathy in Populations of Asian Ancestry," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-1, November.
    13. Markus Draaken & Michael Knapp & Tracie Pennimpede & Johanna M Schmidt & Anne-Karolin Ebert & Wolfgang Rösch & Raimund Stein & Boris Utsch & Karin Hirsch & Thomas M Boemers & Elisabeth Mangold & Stefa, 2015. "Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy," PLOS Genetics, Public Library of Science, vol. 11(3), pages 1-13, March.
    14. Sara L Van Driest & Tracy L McGregor & Digna R Velez Edwards & Ben R Saville & Terrie E Kitchner & Scott J Hebbring & Murray Brilliant & Hayan Jouni & Iftikhar J Kullo & C Buddy Creech & Prince J Kann, 2015. "Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-14, June.
    15. Myoung Keun Lee & John R Shaffer & Elizabeth J Leslie & Ekaterina Orlova & Jenna C Carlson & Eleanor Feingold & Mary L Marazita & Seth M Weinberg, 2017. "Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2," PLOS ONE, Public Library of Science, vol. 12(4), pages 1-13, April.
    16. Benger, Etam & Sella, Guy, 2013. "Modeling the effect of changing selective pressures on polymorphism and divergence," Theoretical Population Biology, Elsevier, vol. 85(C), pages 73-85.
    17. Anu Loukola & Jadwiga Buchwald & Richa Gupta & Teemu Palviainen & Jenni Hällfors & Emmi Tikkanen & Tellervo Korhonen & Miina Ollikainen & Antti-Pekka Sarin & Samuli Ripatti & Terho Lehtimäki & Olli Ra, 2015. "A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism," PLOS Genetics, Public Library of Science, vol. 11(9), pages 1-23, September.
    18. Taru Tukiainen & Matti Pirinen & Antti-Pekka Sarin & Claes Ladenvall & Johannes Kettunen & Terho Lehtimäki & Marja-Liisa Lokki & Markus Perola & Juha Sinisalo & Efthymia Vlachopoulou & Johan G Eriksso, 2014. "Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation," PLOS Genetics, Public Library of Science, vol. 10(2), pages 1-12, February.
    19. Garud, Nandita R. & Rosenberg, Noah A., 2015. "Enhancing the mathematical properties of new haplotype homozygosity statistics for the detection of selective sweeps," Theoretical Population Biology, Elsevier, vol. 102(C), pages 94-101.
    20. Yichen Zheng & Thomas Wiehe, 2019. "Adaptation in structured populations and fuzzy boundaries between hard and soft sweeps," PLOS Computational Biology, Public Library of Science, vol. 15(11), pages 1-32, November.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pbio00:2002458. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosbiology (email available below). General contact details of provider: https://journals.plos.org/plosbiology/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.