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Changing perspectives: Towards detailed phenotyping in genetics

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  • 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.

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  • 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
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    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.
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