Identification and analysis of individuals who deviate from their genetically-predicted phenotype.
Identification and analysis of individuals who deviate from their genetically-predicted phenotype.
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DOI：
10.1371/journal.pgen.1010934
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发表时间：
2023-09
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
全基因组关联研究的结果促进了许多常见人类表型的遗传预测因子的产生。根据常见变异对与遗传预测因子不一致的个体进行分层，对于旨在确定替代因果因素的后续研究可能很重要。使用全基因组估算的遗传数据，我们的目的是将来自英国生物库的158，951名无关个体分类为一致或偏离两种测量良好的表型。我们首先将我们的方法应用于站立高度：我们的初步分析将244名个体（0.15%）归类为与其遗传预测身高不一致。我们发现，这些人在10岁时自我报告比平均水平矮或高，诊断为先天性畸形，以及以前归类为生长障碍原因的基因中罕见的功能丧失变异。其次，我们将我们的方法应用于LDL胆固醇（LDL-C）。我们将156名（0.12%）个体分类为与其遗传预测的LDL-C不一致，并表明这些个体富含临床可操作的心血管风险因素和先前显示参与代谢过程的基因中的罕见遗传变异。LDL-C高于基于遗传预测因子的预期的个体也具有更高的发生冠状动脉疾病和2型糖尿病的风险，即使在校正了测量的LDL-C，BMI和年龄之后，这表明与遗传预测的LDL-C的向上偏差指示一般健康状况不佳。我们的研究结果保持广泛一致时，进行敏感性分析的基础上，各种参数和非参数的方法来定义偏离多基因的期望的个人。我们的分析表明，根据遗传预测的偏差定量识别个体以进行进一步随访的潜在重要性。由于大规模遗传关联研究的发现和遗传预测因子能力的进步，人类遗传学在帮助预测人群中的人类特征方面变得越来越有用。这提供了一个机会，以潜在地确定个人偏离遗传预测的共同表型的调查。例如，一个人可能被遗传预测为高，但比预期的要矮。识别偏离遗传预测的个体可能很重要，因为这可以促进进一步的后续行动，以评估可能的原因。使用来自英国生物库的158，951名无关个体，以身高和LDL胆固醇作为范例特征，我们证明了大约0.15%和0.12%的个体分别偏离了他们的遗传预测表型。我们观察到这些个体富集了一系列罕见的临床诊断，以及可能是因果关系的罕见遗传因素。我们的分析还展示了几种检测偏离遗传预测的个体的方法，这些方法可以应用于一系列连续的人类表型。
Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol (LDL-C). We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL-C and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions. Human genetics is becoming increasingly useful to help predict human traits across a population owing to findings from large-scale genetic association studies and advances in the power of genetic predictors. This provides an opportunity to potentially identify individuals that deviate from genetic predictions for a common phenotype under investigation. For example, an individual may be genetically predicted to be tall, but be shorter than expected. It is potentially important to identify individuals who deviate from genetic predictions as this can facilitate further follow-up to assess likely causes. Using 158,951 unrelated individuals from the UK Biobank, with height and LDL cholesterol as exemplar traits, we demonstrate that approximately 0.15% and 0.12% of individuals deviate from their genetically predicted phenotypes, respectively. We observed these individuals to be enriched for a range of rare clinical diagnoses, as well as rare genetic factors that may be causal. Our analyses also demonstrate several methods for detecting individuals who deviate from genetic predictions that can be applied to a range of continuous human phenotypes.
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影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
2
作者：
Muthen, Bengt;Asparouhov, Tihomir
通讯作者：
Asparouhov, Tihomir
影响因子：
64.8
作者：
Graham SE;Clarke SL;Wu KH;Kanoni S;Zajac GJM;Ramdas S;Surakka I;Ntalla I;Vedantam S;Winkler TW;Locke AE;Marouli E;Hwang MY;Han S;Narita A;Choudhury A;Bentley AR;Ekoru K;Verma A;Trivedi B;Martin HC;Hunt KA;Hui Q;Klarin D;Zhu X;Thorleifsson G;Helgadottir A;Gudbjartsson DF;Holm H;Olafsson I;Akiyama M;Sakaue S;Terao C;Kanai M;Zhou W;Brumpton BM;Rasheed H;Ruotsalainen SE;Havulinna AS;Veturi Y;Feng Q;Rosenthal EA;Lingren T;Pacheco JA;Pendergrass SA;Haessler J;Giulianini F;Bradford Y;Miller JE;Campbell A;Lin K;Millwood IY;Hindy G;Rasheed A;Faul JD;Zhao W;Weir DR;Turman C;Huang H;Graff M;Mahajan A;Brown MR;Zhang W;Yu K;Schmidt EM;Pandit A;Gustafsson S;Yin X;Luan J;Zhao JH;Matsuda F;Jang HM;Yoon K;Medina-Gomez C;Pitsillides A;Hottenga JJ;Willemsen G;Wood AR;Ji Y;Gao Z;Haworth S;Mitchell RE;Chai JF;Aadahl M;Yao J;Manichaikul A;Warren HR;Ramirez J;Bork-Jensen J;Kårhus LL;Goel A;Sabater-Lleal M;Noordam R;Sidore C;Fiorillo E;McDaid AF;Marques-Vidal P;Wielscher M;Trompet S;Sattar N;Møllehave LT;Thuesen BH;Munz M;Zeng L;Huang J;Yang B;Poveda A;Kurbasic A;Lamina C;Forer L;Scholz M;Galesloot TE;Bradfield JP;Daw EW;Zmuda JM;Mitchell JS;Fuchsberger C;Christensen H;Brody JA;Feitosa MF;Wojczynski MK;Preuss M;Mangino M;Christofidou P;Verweij N;Benjamins JW;Engmann J;Kember RL;Slieker RC;Lo KS;Zilhao NR;Le P;Kleber ME;Delgado GE;Huo S;Ikeda DD;Iha H;Yang J;Liu J;Leonard HL;Marten J;Schmidt B;Arendt M;Smyth LJ;Cañadas-Garre M;Wang C;Nakatochi M;Wong A;Hutri-Kähönen N;Sim X;Xia R;Huerta-Chagoya A;Fernandez-Lopez JC;Lyssenko V;Ahmed M;Jackson AU;Yousri NA;Irvin MR;Oldmeadow C;Kim HN;Ryu S;Timmers PRHJ;Arbeeva L;Dorajoo R;Lange LA;Chai X;Prasad G;Lorés-Motta L;Pauper M;Long J;Li X;Theusch E;Takeuchi F;Spracklen CN;Loukola A;Bollepalli S;Warner SC;Wang YX;Wei WB;Nutile T;Ruggiero D;Sung YJ;Hung YJ;Chen S;Liu F;Yang J;Kentistou KA;Gorski M;Brumat M;Meidtner K;Bielak LF;Smith JA;Hebbar P;Farmaki AE;Hofer E;Lin M;Xue C;Zhang J;Concas MP;Vaccargiu S;van der Most PJ;Pitkänen N;Cade BE;Lee J;van der Laan SW;Chitrala KN;Weiss S;Zimmermann ME;Lee JY;Choi HS;Nethander M;Freitag-Wolf S;Southam L;Rayner NW;Wang CA;Lin SY;Wang JS;Couture C;Lyytikäinen LP;Nikus K;Cuellar-Partida G;Vestergaard H;Hildalgo B;Giannakopoulou O;Cai Q;Obura MO;van Setten J;Li X;Schwander K;Terzikhan N;Shin JH;Jackson RD;Reiner AP;Martin LW;Chen Z;Li L;Highland HM;Young KL;Kawaguchi T;Thiery J;Bis JC;Nadkarni GN;Launer LJ;Li H;Nalls MA;Raitakari OT;Ichihara S;Wild SH;Nelson CP;Campbell H;Jäger S;Nabika T;Al-Mulla F;Niinikoski H;Braund PS;Kolcic I;Kovacs P;Giardoglou T;Katsuya T;Bhatti KF;de Kleijn D;de Borst GJ;Kim EK;Adams HHH;Ikram MA;Zhu X;Asselbergs FW;Kraaijeveld AO;Beulens JWJ;Shu XO;Rallidis LS;Pedersen O;Hansen T;Mitchell P;Hewitt AW;Kähönen M;Pérusse L;Bouchard C;Tönjes A;Chen YI;Pennell CE;Mori TA;Lieb W;Franke A;Ohlsson C;Mellström D;Cho YS;Lee H;Yuan JM;Koh WP;Rhee SY;Woo JT;Heid IM;Stark KJ;Völzke H;Homuth G;Evans MK;Zonderman AB;Polasek O;Pasterkamp G;Hoefer IE;Redline S;Pahkala 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BM;Brandslund I;Pramstaller PP;Christensen K;Ripatti S;Widén E;Hakonarson H;Grant SFA;Kiemeney LALM;de Graaf J;Loeffler M;Kronenberg F;Gu D;Erdmann J;Schunkert H;Franks PW;Linneberg A;Jukema JW;Khera AV;Männikkö M;Jarvelin MR;Kutalik Z;Cucca F;Mook-Kanamori DO;van Dijk KW;Watkins H;Strachan DP;Grarup N;Sever P;Poulter N;Rotter JI;Dantoft TM;Karpe F;Neville MJ;Timpson NJ;Cheng CY;Wong TY;Khor CC;Sabanayagam C;Peters A;Gieger C;Hattersley AT;Pedersen NL;Magnusson PKE;Boomsma DI;de Geus EJC;Cupples LA;van Meurs JBJ;Ghanbari M;Gordon-Larsen P;Huang W;Kim YJ;Tabara Y;Wareham NJ;Langenberg C;Zeggini E;Kuusisto J;Laakso M;Ingelsson E;Abecasis G;Chambers JC;Kooner JS;de Vries PS;Morrison AC;North KE;Daviglus M;Kraft P;Martin NG;Whitfield JB;Abbas S;Saleheen D;Walters RG;Holmes MV;Black C;Smith BH;Justice AE;Baras A;Buring JE;Ridker PM;Chasman DI;Kooperberg C;Wei WQ;Jarvik GP;Namjou B;Hayes MG;Ritchie MD;Jousilahti P;Salomaa V;Hveem K;Åsvold BO;Kubo M;Kamatani Y;Okada Y;Murakami 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通讯作者：
Willer CJ
影响因子：
64.8
作者：
Joshi PK;Esko T;Mattsson H;Eklund N;Gandin I;Nutile T;Jackson AU;Schurmann C;Smith AV;Zhang W;Okada Y;Stančáková A;Faul JD;Zhao W;Bartz TM;Concas MP;Franceschini N;Enroth S;Vitart V;Trompet S;Guo X;Chasman DI;O'Connel JR;Corre T;Nongmaithem SS;Chen Y;Mangino M;Ruggiero D;Traglia M;Farmaki AE;Kacprowski T;Bjonnes A;van der Spek A;Wu Y;Giri AK;Yanek LR;Wang L;Hofer E;Rietveld CA;McLeod O;Cornelis MC;Pattaro C;Verweij N;Baumbach C;Abdellaoui A;Warren HR;Vuckovic D;Mei H;Bouchard C;Perry JRB;Cappellani S;Mirza SS;Benton MC;Broeckel U;Medland SE;Lind PA;Malerba G;Drong A;Yengo L;Bielak LF;Zhi D;van der Most PJ;Shriner D;Mägi R;Hemani G;Karaderi T;Wang Z;Liu T;Demuth I;Zhao JH;Meng W;Lataniotis L;van der Laan SW;Bradfield JP;Wood AR;Bonnefond A;Ahluwalia TS;Hall LM;Salvi E;Yazar S;Carstensen L;de Haan HG;Abney M;Afzal U;Allison MA;Amin N;Asselbergs FW;Bakker SJL;Barr RG;Baumeister SE;Benjamin DJ;Bergmann S;Boerwinkle E;Bottinger EP;Campbell A;Chakravarti A;Chan Y;Chanock SJ;Chen C;Chen YI;Collins FS;Connell J;Correa A;Cupples LA;Smith GD;Davies G;Dörr M;Ehret G;Ellis SB;Feenstra B;Feitosa MF;Ford I;Fox CS;Frayling TM;Friedrich N;Geller F;Scotland G;Gillham-Nasenya I;Gottesman O;Graff M;Grodstein F;Gu C;Haley C;Hammond CJ;Harris SE;Harris TB;Hastie ND;Heard-Costa NL;Heikkilä K;Hocking LJ;Homuth G;Hottenga JJ;Huang J;Huffman JE;Hysi PG;Ikram MA;Ingelsson E;Joensuu A;Johansson Å;Jousilahti P;Jukema JW;Kähönen M;Kamatani Y;Kanoni S;Kerr SM;Khan NM;Koellinger P;Koistinen HA;Kooner MK;Kubo M;Kuusisto J;Lahti J;Launer LJ;Lea RA;Lehne B;Lehtimäki T;Liewald DCM;Lind L;Loh M;Lokki ML;London SJ;Loomis SJ;Loukola A;Lu Y;Lumley T;Lundqvist A;Männistö S;Marques-Vidal P;Masciullo C;Matchan A;Mathias RA;Matsuda K;Meigs JB;Meisinger C;Meitinger T;Menni C;Mentch FD;Mihailov E;Milani L;Montasser ME;Montgomery GW;Morrison A;Myers RH;Nadukuru R;Navarro P;Nelis M;Nieminen MS;Nolte IM;O'Connor GT;Ogunniyi A;Padmanabhan S;Palmas WR;Pankow JS;Patarcic I;Pavani F;Peyser PA;Pietilainen K;Poulter N;Prokopenko I;Ralhan S;Redmond P;Rich SS;Rissanen H;Robino A;Rose LM;Rose R;Sala C;Salako B;Salomaa V;Sarin AP;Saxena R;Schmidt H;Scott LJ;Scott WR;Sennblad B;Seshadri S;Sever P;Shrestha S;Smith BH;Smith JA;Soranzo N;Sotoodehnia N;Southam L;Stanton AV;Stathopoulou MG;Strauch K;Strawbridge RJ;Suderman MJ;Tandon N;Tang ST;Taylor KD;Tayo BO;Töglhofer AM;Tomaszewski M;Tšernikova N;Tuomilehto J;Uitterlinden AG;Vaidya D;van Hylckama Vlieg A;van Setten J;Vasankari T;Vedantam S;Vlachopoulou E;Vozzi D;Vuoksimaa E;Waldenberger M;Ware EB;Wentworth-Shields W;Whitfield JB;Wild S;Willemsen G;Yajnik CS;Yao J;Zaza G;Zhu X;Project TBJ;Salem RM;Melbye M;Bisgaard H;Samani NJ;Cusi D;Mackey DA;Cooper RS;Froguel P;Pasterkamp G;Grant SFA;Hakonarson H;Ferrucci L;Scott RA;Morris AD;Palmer CNA;Dedoussis G;Deloukas P;Bertram L;Lindenberger U;Berndt SI;Lindgren CM;Timpson NJ;Tönjes A;Munroe PB;Sørensen TIA;Rotimi CN;Arnett DK;Oldehinkel AJ;Kardia SLR;Balkau B;Gambaro G;Morris AP;Eriksson JG;Wright MJ;Martin NG;Hunt SC;Starr JM;Deary IJ;Griffiths LR;Tiemeier H;Pirastu N;Kaprio J;Wareham NJ;Pérusse L;Wilson JG;Girotto G;Caulfield MJ;Raitakari O;Boomsma DI;Gieger C;van der Harst P;Hicks AA;Kraft P;Sinisalo J;Knekt P;Johannesson M;Magnusson PKE;Hamsten A;Schmidt R;Borecki IB;Vartiainen E;Becker DM;Bharadwaj D;Mohlke KL;Boehnke M;van Duijn CM;Sanghera DK;Teumer A;Zeggini E;Metspalu A;Gasparini P;Ulivi S;Ober C;Toniolo D;Rudan I;Porteous DJ;Ciullo M;Spector TD;Hayward C;Dupuis J;Loos RJF;Wright AF;Chandak GR;Vollenweider P;Shuldiner A;Ridker PM;Rotter JI;Sattar N;Gyllensten U;North KE;Pirastu M;Psaty BM;Weir DR;Laakso M;Gudnason V;Takahashi A;Chambers JC;Kooner JS;Strachan DP;Campbell H;Hirschhorn JN;Perola M;Polašek O;Wilson JF
通讯作者：
Wilson JF