Computational methods to dissect the genetic basis of human disease by Kim, Samuel Sungil

“…In the second chapter, I investigate the shared genetic architecture between Mendelian disease and common disease by developing a machine learning framework to impute and denoise Mendelian disease-derived pathogenicity scores. …”
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Selecting instruments for Mendelian randomization in the wake of genome-wide association studies by Swerdlow, D, Kuchenbaecker, K, Shah, S, Sofat, R, Holmes, M, White, J, Mindell, J, Kivimaki, M, Brunner, E, Whittaker, J, Casas, J, Hingorani, A

“…We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. …”

BIRC6 modifies risk of invasive bacterial infection in Kenyan children by Gilchrist, JJ, Kariuki, SN, Watson, JA, Band, G, Uyoga, S, Ndila, CM, Mturi, N, Mwarumba, S, Mohammed, S, Mosobo, M, Alasoo, K, Rockett, KA, Mentzer, AJ, Kwiatkowski, DP, Hill, AVS, Maitland, K, Scott, JAG, Williams, TN

“…In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here, we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with Plasmodium falciparum parasitaemia. …”

Lack of genetic support for shared aetiology of Coronary Artery Disease and Late-onset Alzheimer’s disease by Grace, PC, Clarke, R, Goel, A, Farrall, M, Watkins, H, Hopewell, JC

“…This Mendelian randomization study indicates that the APOE locus is the chief determinant of shared genetic architecture between CAD and LOAD, and suggests a lack of causal relevance of CAD for risk of LOAD after exclusion of APOE.…”

Genome-wide association analysis of imputed rare variants: application to seven common complex diseases. by Mägi, R, Asimit, J, Day-Williams, A, Zeggini, E, Morris, A

“…The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.…”

Lifetime reproductive success and heritability in nature by Merila, J, Sheldon, B

“…Our results are consistent with earlier suggestions that fitness-related traits may have more complex genetic architecture than traits more distantly associated with fitness.…”

Heterozygosity is unrelated to adult fitness measures in a large, noninbred population of great tits (Parus major). by Chapman, JR, Sheldon, B

“…The extent to which heterozygosity-fitness correlations (HFCs) are expected in wild populations is an important and unresolved question in evolutionary biology, because it relates to our understanding of the genetic architecture of fitness. Here, we report a study of HFCs in a wild, noninbred population of great tits (Parus major), based on a sample comprising 281 individuals typed at 26 markers, resulting in a data set comprising over 5600 genotypes. …”

Host–parasite coevolution and the stability of genetic kin recognition by Scott, TW, Grafen, A, West, SA

“…However, we show that if the genetic architecture is allowed to evolve, meaning natural selection can choose the recognition locus, genetic kin recognition is more likely to be stable. …”

Optix and cortex/ivory/mir-193 again: the repeated use of two mimicry hotspot loci by Orteu, A, Hornett, EA, Reynolds, LA, Warren, IA, Hurst, GDD, Martin, SH, Jiggins, CD

“…By dissecting the genetic architecture of mimicry in Hypolimnas misippus and Hypolimnas bolina, we present evidence that distinct non-coding regions control the development of white pattern elements in the forewing and hindwing of the two species, suggesting independent evolution, and that no structural variation is found at the locus. …”

Identification of shared genetic variants between schizophrenia and lung cancer. by Zuber, V, Jönsson, E, Frei, O, Witoelar, A, Thompson, W, Schork, A, Bettella, F, Wang, Y, Djurovic, S, Smeland, O, Dieset, I, Fanous, A, Desikan, R, Küry, S, Bézieau, S, Dale, A, Mills, I, Andreassen, O

“…We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. …”

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. by Tsoi, L, Spain, S, Knight, J, Ellinghaus, E, Stuart, P, Capon, F, Ding, J, Li, Y, Tejasvi, T, Gudjonsson, J, Kang, H, Allen, M, McManus, R, Novelli, G, Samuelsson, L, Schalkwijk, J, Ståhle, M, Burden, A, Smith, C, Cork, M, Estivill, X, Bowcock, A, Krueger, G, Weger, W, Worthington, J

“…To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. …”

Imaging Cardiac Developmental Malformations in the Mouse Embryo by Mohun, T, Weninger, W, Bhattacharya, S

“…Studies of human genetic architecture cannot provide a mechanistic understanding of gene function in cardiac development, and analysis of gene-gene and gene-environment interactions in humans remains a challenge. …”

Effects of spontaneous mutation accumulation on sex ratio traits in a parasitoid wasp. by Pannebakker, B, Halligan, D, Reynolds, K, Ballantyne, G, Shuker, D, Barton, N, West, SA

“…However, we know rather little about the underlying genetics of sex ratio or how genetic architecture might constrain adaptive sex-ratio behavior. …”

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume by Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, Smith, G, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bønnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B, UK10K consortium, Bhattacharya, S

“…Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. …”

A meta-analysis of genome-wide association studies identifies multiple longevity genes by Deelen, J, Evans, DS, Arking, DE, Tesi, N, Nygaard, M, Liu, X, Wojczynski, MK, Biggs, ML, Van Der Spek, A, Atzmon, G, Ware, EB, Sarnowski, C, Smith, AV, Seppälä, I, Cordell, HJ, Dose, J, Amin, N, Arnold, AM, Ayers, KL, Barzilai, N, Becker, EJ, Beekman, M, Blanché, H, Christensen, K, Christiansen, L

“…Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.…”

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity by Tsoi, L, Tsoi, L, Spain, S, Spain, S, Knight, J, Knight, J, Knight, J, Ellinghaus, E, Ellinghaus, E, Stuart, P, Capon, F, Ding, J, Li, Y, Tejasvi, T, Gudjonsson, J, Kang, H, Allen, M, McManus, R, McManus, R, Novelli, G, Novelli, G, Samuelsson, L, Schalkwijk, J, Ståhle, M, Burden, A

“…To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. …”

"Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. by Goriely, A, McGrath, J, Hultman, C, Wilkie, A, Malaspina, D

“…This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. …”

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors by Bakker, MK, van der Spek, RAA, van Rheenen, W, Walters, RG, Millwood, IY

“…To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. …”

Genetic predisposition to coronary artery disease in type 2 diabetes by van Zuydam, NR, Ladenvall, C, Voight, BF, Strawbridge, RJ, Fernandez Tajes, J, Rayner, NW, Robertson, NR, Mahajan, A, Vlachopoulou, E, Goel, A, Kleber, ME, Nelson, CP, Kwee, LC, Esko, T, Mihailov, E, Mägi, R, Milani, L, Fischer, K, Kanoni, S, Kumar, J, Song, C, Hartiala, JA, Pedersen, NL, Perola, M, Gieger, C, Peters, A, Qu, L, Willems, SM, Doney, ASF, Morris, AD, Zheng, Y, Sesti, G, Hu, FB, Qi, L, Laakso, M, Thorsteinsdottir, U, Grallert, H, van Duijn, C, Reilly, MP, Ingelsson, E, Deloukas, P, Kathiresan, S, Metspalu, A, Shah, SH, Sinisalo, J, Salomaa, V, Hamsten, A, Samani, NJ, März, W, Hazen, SL, Watkins, H

“…Conclusions - This study found no evidence that the genetic architecture of CAD differs in those with T2D compared to those without T2D. …”

Lack of evidence for intermolecular epistatic interactions between adiponectin and resistin gene polymorphisms in Malaysian male subjects by Lau, C.H., Muniandy, S.

“…Epistasis (gene-gene interaction) is a ubiquitous component of the genetic architecture of complex traits such as susceptibility to common human diseases. …”
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