IDEAS home Printed from https://ideas.repec.org/p/osf/thesis/a4nz2_v1.html
   My bibliography  Save this paper

Changing perspectives: Towards detailed phenotyping in genetics

Author

Listed:
  • Nagel, Mats

Abstract

Mental health problems are highly prevalent in modern-day society. Despite several decades of intensive research aimed at identifying the underlying biological mechanisms, and potential drug targets, pharmacological treatments still have limited success. Since all traits are at least partially influenced by our genetic makeup, using genetic information to increase our understanding of the biological mechanisms underlying mental health problems might eventually benefit patients. Genome-wide association studies (GWAS) provide an exploratory way to identify genetic variants throughout the genome that are, statistically, associated to a trait of interest. The explosion of GWAS studies since 2005 (https://www.ebi.ac.uk/gwas/diagram) has drastically increased our knowledge of the biology of diseases and identified thousands of variants involved in a wide variety of (disease) traits. Yet for many complex traits, like psychiatric disorders, the identified genetic variants explain only a fraction of the variance in the trait. We argue that this may, in part, be the result of the way in which neuropsychiatric traits are operationalized in genetic studies. Typically, participants are classified as cases (i.e., people that suffer from a given psychiatric disorder) or as controls (i.e., not suffering from that particular disorder). However, people suffering from the same disorder may exhibit different sets of symptoms that may, in turn, be influenced by different genetic variants. In other words, the manner in which phenotypes are operationalized will have consequences for the success of genetic analyses. Therefore, in order to properly study the genetic basis of complex behavior, it is vital to think about the exact nature of the phenotypes used in the analysis, and the way they are operationalized. This thesis uses large-scale genetic data and state-of-the-art methods to study the merits of more detailed phenotyping in uncovering the genetics of complex neuropsychiatric traits.

Suggested Citation

  • Nagel, Mats, 2020. "Changing perspectives: Towards detailed phenotyping in genetics," Thesis Commons a4nz2_v1, Center for Open Science.
    • Handle: RePEc:osf:thesis:a4nz2_v1
    DOI: 10.31219/osf.io/a4nz2_v1
    as

    Download full text from publisher

    File URL: https://osf.io/download/5eabe61776188b02f3914edc/
    Download Restriction: no
    File URL: https://libkey.io/10.31219/osf.io/a4nz2_v1?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. René H. Medema & Geert J. P. L. Kops & Johannes L. Bos & Boudewijn M. T. Burgering, 2000. "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1," Nature, Nature, vol. 404(6779), pages 782-787, April.
    2. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    3. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    4. Eric S. Lander, 2011. "Initial impact of the sequencing of the human genome," Nature, Nature, vol. 470(7333), pages 187-197, February.
    5. Derrek P. Hibar & Jason L. Stein & Miguel E. Renteria & Alejandro Arias-Vasquez & Sylvane Desrivières & Neda Jahanshad & Roberto Toro & Katharina Wittfeld & Lucija Abramovic & Micael Andersson & Benja, 2015. "Common genetic variants influence human subcortical brain structures," Nature, Nature, vol. 520(7546), pages 224-229, April.
    6. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    7. Irving Kirsch & Brett J Deacon & Tania B Huedo-Medina & Alan Scoboria & Thomas J Moore & Blair T Johnson, 2008. "Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration," PLOS Medicine, Public Library of Science, vol. 5(2), pages 1-9, February.
    8. Zhihong Zhu & Zhili Zheng & Futao Zhang & Yang Wu & Maciej Trzaskowski & Robert Maier & Matthew R. Robinson & John J. McGrath & Peter M. Visscher & Naomi R. Wray & Jian Yang, 2018. "Causal associations between risk factors and common diseases inferred from GWAS summary data," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    9. Aysu Okbay & Jonathan P. Beauchamp & Mark Alan Fontana & James J. Lee & Tune H. Pers & Cornelius A. Rietveld & Patrick Turley & Guo-Bo Chen & Valur Emilsson & S. Fleur W. Meddens & Sven Oskarsson & Jo, 2016. "Genome-wide association study identifies 74 loci associated with educational attainment," Nature, Nature, vol. 533(7604), pages 539-542, May.
    10. Christiaan A. Leeuw & Sven Stringer & Ilona A. Dekkers & Tom Heskes & Danielle Posthuma, 2018. "Conditional and interaction gene-set analysis reveals novel functional pathways for blood pressure," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    11. Eirini Marouli & Mariaelisa Graff & Carolina Medina-Gomez & Ken Sin Lo & Andrew R. Wood & Troels R. Kjaer & Rebecca S. Fine & Yingchang Lu & Claudia Schurmann & Heather M. Highland & Sina Rüeger & Gud, 2017. "Rare and low-frequency coding variants alter human adult height," Nature, Nature, vol. 542(7640), pages 186-190, February.
    12. Adam E. Locke & Bratati Kahali & Sonja I. Berndt & Anne E. Justice & Tune H. Pers & Felix R. Day & Corey Powell & Sailaja Vedantam & Martin L. Buchkovich & Jian Yang & Damien C. Croteau-Chonka & Tonu , 2015. "Genetic studies of body mass index yield new insights for obesity biology," Nature, Nature, vol. 518(7538), pages 197-206, February.
    13. Anne E. Justice & Thomas W. Winkler & Mary F. Feitosa & Misa Graff & Virginia A. Fisher & Kristin Young & Llilda Barata & Xuan Deng & Jacek Czajkowski & David Hadley & Julius S. Ngwa & Tarunveer S. Ah, 2017. "Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits," Nature Communications, Nature, vol. 8(1), pages 1-19, April.
    14. Karsten Suhre & Matthias Arnold & Aditya Mukund Bhagwat & Richard J. Cotton & Rudolf Engelke & Johannes Raffler & Hina Sarwath & Gaurav Thareja & Annika Wahl & Robert Kirk DeLisle & Larry Gold & Marij, 2017. "Erratum: Connecting genetic risk to disease end points through the human blood plasma proteome," Nature Communications, Nature, vol. 8(1), pages 1-1, April.
    15. Simon Haworth & Chin Yang Shapland & Caroline Hayward & Bram P. Prins & Janine F. Felix & Carolina Medina-Gomez & Fernando Rivadeneira & Carol Wang & Tarunveer S. Ahluwalia & Martine Vrijheid & Mònica, 2019. "Low-frequency variation in TP53 has large effects on head circumference and intracranial volume," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    16. Brendan Maher, 2008. "Personal genomes: The case of the missing heritability," Nature, Nature, vol. 456(7218), pages 18-21, November.
    17. Magnus Johannesson & David I. Laibson & Sarah E. Medland & Michelle N. Meyer & Joseph K. Pickrell & Tõnu Esko & Robert F. Krueger & Jonathan P. Beauchamp & Philipp D. Koellinger & Daniel J. Benjamin &, 2016. "Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses," Post-Print hal-02017373, HAL.
    18. Karsten Suhre & Matthias Arnold & Aditya Mukund Bhagwat & Richard J. Cotton & Rudolf Engelke & Johannes Raffler & Hina Sarwath & Gaurav Thareja & Annika Wahl & Robert Kirk DeLisle & Larry Gold & Marij, 2017. "Connecting genetic risk to disease end points through the human blood plasma proteome," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    19. Gad Abraham & Michael Inouye, 2014. "Fast Principal Component Analysis of Large-Scale Genome-Wide Data," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-5, April.
    20. Mats Nagel & Kyoko Watanabe & Sven Stringer & Danielle Posthuma & Sophie Sluis, 2018. "Item-level analyses reveal genetic heterogeneity in neuroticism," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    21. Chuong B Do & Joyce Y Tung & Elizabeth Dorfman & Amy K Kiefer & Emily M Drabant & Uta Francke & Joanna L Mountain & Samuel M Goldman & Caroline M Tanner & J William Langston & Anne Wojcicki & Nicholas, 2011. "Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease," PLOS Genetics, Public Library of Science, vol. 7(6), pages 1-14, June.
    22. Lee, James J. & McGue, Matt & Iacono, William G. & Michael, Andrew M. & Chabris, Christopher F., 2019. "The causal influence of brain size on human intelligence: Evidence from within-family phenotypic associations and GWAS modeling," Intelligence, Elsevier, vol. 75(C), pages 48-58.
    23. Chabris, C. F. & Lee, J. J. & Cesarini, D. & Benjamin, D. J. & Laibson, David I., 2015. "The Fourth Law of Behavior Genetics," Scholarly Articles 30780203, Harvard University Department of Economics.
    24. Chao Tian & Robert M Plenge & Michael Ransom & Annette Lee & Pablo Villoslada & Carlo Selmi & Lars Klareskog & Ann E Pulver & Lihong Qi & Peter K Gregersen & Michael F Seldin, 2008. "Analysis and Application of European Genetic Substructure Using 300 K SNP Information," PLOS Genetics, Public Library of Science, vol. 4(1), pages 1-11, January.
    25. Robert Plomin, 1999. "Genetics and general cognitive ability," Nature, Nature, vol. 402(6761), pages 25-29, December.
    Full references (including those not matched with items on IDEAS)

    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. Nagel, Mats, 2020. "Changing perspectives: Towards detailed phenotyping in genetics," Thesis Commons a4nz2, Center for Open Science.
    2. Cornelius A. Rietveld & Eric A.W. Slob & A. Roy Thurik, 2021. "A decade of research on the genetics of entrepreneurship: a review and view ahead," Small Business Economics, Springer, vol. 57(3), pages 1303-1317, October.
    3. Charley Xia & Sarah J. Pickett & David C. M. Liewald & Alexander Weiss & Gavin Hudson & W. David Hill, 2023. "The contributions of mitochondrial and nuclear mitochondrial genetic variation to neuroticism," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Priya Gupta & Marco Galimberti & Yue Liu & Sarah Beck & Aliza Wingo & Thomas Wingo & Keyrun Adhikari & Henry R. Kranzler & Murray B. Stein & Joel Gelernter & Daniel F. Levey, 2024. "A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology," Nature Human Behaviour, Nature, vol. 8(11), pages 2235-2249, November.
    5. William R. Reay & Michael P. Geaghan & Murray J. Cairns, 2022. "The genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Ashley Budu-Aggrey & Anna Kilanowski & Maria K. Sobczyk & Suyash S. Shringarpure & Ruth Mitchell & Kadri Reis & Anu Reigo & Reedik Mägi & Mari Nelis & Nao Tanaka & Ben M. Brumpton & Laurent F. Thomas , 2023. "European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Lili Liu & Atlas Khan & Elena Sanchez-Rodriguez & Francesca Zanoni & Yifu Li & Nicholas Steers & Olivia Balderes & Junying Zhang & Priya Krithivasan & Robert A. LeDesma & Clara Fischman & Scott J. Heb, 2022. "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Shahram Bahrami & Kaja Nordengen & Jaroslav Rokicki & Alexey A. Shadrin & Zillur Rahman & Olav B. Smeland & Piotr P. Jaholkowski & Nadine Parker & Pravesh Parekh & Kevin S. O’Connell & Torbjørn Elvsås, 2024. "The genetic landscape of basal ganglia and implications for common brain disorders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Mathias Seviiri & Matthew H. Law & Jue-Sheng Ong & Puya Gharahkhani & Pierre Fontanillas & Catherine M. Olsen & David C. Whiteman & Stuart MacGregor, 2022. "A multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    10. Zhen Qiao & Julia Sidorenko & Joana A. Revez & Angli Xue & Xueling Lu & Katri Pärna & Harold Snieder & Peter M. Visscher & Naomi R. Wray & Loic Yengo, 2023. "Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    11. Dixon, Padraig & Hollingworth, William & Harrison, Sean & Davies, Neil M. & Davey Smith, George, 2020. "Mendelian Randomization analysis of the causal effect of adiposity on hospital costs," Journal of Health Economics, Elsevier, vol. 70(C).
    12. 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).
    13. Xiaofeng Zhu & Yihe Yang & Noah Lorincz-Comi & Gen Li & Amy R. Bentley & Paul S. de Vries & Michael Brown & Alanna C. Morrison & Charles N. Rotimi & W. James Gauderman & Dabeeru C. Rao & Hugues Aschar, 2024. "An approach to identify gene-environment interactions and reveal new biological insight in complex traits," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Sophie A. Riesmeijer & Zoha Kamali & Michael Ng & Dmitriy Drichel & Bram Piersma & Kerstin Becker & Thomas B. Layton & Jagdeep Nanchahal & Michael Nothnagel & Ahmad Vaez & Hans Christian Hennies & Pau, 2024. "A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    15. Zhiqiang Sha & Dick Schijven & Amaia Carrion-Castillo & Marc Joliot & Bernard Mazoyer & Simon E. Fisher & Fabrice Crivello & Clyde Francks, 2021. "The genetic architecture of structural left–right asymmetry of the human brain," Nature Human Behaviour, Nature, vol. 5(9), pages 1226-1239, September.
    16. Gianmarco Mignogna & Caitlin E. Carey & Robbee Wedow & Nikolas Baya & Mattia Cordioli & Nicola Pirastu & Rino Bellocco & Kathryn Fiuza Malerbi & Michel G. Nivard & Benjamin M. Neale & Raymond K. Walte, 2023. "Patterns of item nonresponse behaviour to survey questionnaires are systematic and associated with genetic loci," Nature Human Behaviour, Nature, vol. 7(8), pages 1371-1387, August.
    17. Richard Burns & William J. Young & Nay Aung & Luis R. Lopes & Perry M. Elliott & Petros Syrris & Roberto Barriales-Villa & Catrin Sohrabi & Steffen E. Petersen & Julia Ramírez & Alistair Young & Patri, 2024. "Genetic basis of right and left ventricular heart shape," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    18. Hung-Lin Chen & Hsiu-Yin Chiang & David Ray Chang & Chi-Fung Cheng & Charles C. N. Wang & Tzu-Pin Lu & Chien-Yueh Lee & Amrita Chattopadhyay & Yu-Ting Lin & Che-Chen Lin & Pei-Tzu Yu & Chien-Fong Huan, 2024. "Discovery and prioritization of genetic determinants of kidney function in 297,355 individuals from Taiwan and Japan," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Milton Pividori & Sumei Lu & Binglan Li & Chun Su & Matthew E. Johnson & Wei-Qi Wei & Qiping Feng & Bahram Namjou & Krzysztof Kiryluk & Iftikhar J. Kullo & Yuan Luo & Blair D. Sullivan & Benjamin F. V, 2023. "Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. Yu Huang & Denis Plotnikov & Huan Wang & Danli Shi & Cong Li & Xueli Zhang & Xiayin Zhang & Shulin Tang & Xianwen Shang & Yijun Hu & Honghua Yu & Hongyang Zhang & Jeremy A. Guggenheim & Mingguang He, 2024. "GWAS-by-subtraction reveals an IOP-independent component of primary open angle glaucoma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

    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:osf:thesis:a4nz2_v1. 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: OSF (email available below). General contact details of provider: https://thesiscommons.org .

    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.