Comparing the association between genetic variants and expression on a gene and transcript level
Douglas Wightman & Danielle Posthuma

Genome wide association studies (GWAS) use expression quantitative trait loci (eQTLs) to help connect variants associated with a phenotype to a specific gene. eQTLs are genetic variants that affect how much a gene is expressed. Genes encode multiple versions (transcripts) and these transcripts are abundant in different quantities in different cell types. eQTLs can therefore be measured for expression of a single transcript or on a gene-level (an average of the transcripts). Most GWAS use gene-level eQTLs to connect variants to genes and may be missing transcript specific effects. This project will estimate the local genetic correlation between gene-level eQTLs and transcript level eQTLs using the eQTL catalogue data. Then, transcripts that show distinct eQTLs to gene level data will be identified. These transcript specific eQTLs will be used to connect genetic variants associated with diseases to specific transcripts. This data then may give an insight into which cell types are relevant to the GWAS phenotype. This project is entirely computational and will require the use of bash scripting in a UNIX environment and R (or python). The statistical associations will be determined using a regression framework.

Causal and phenome-wide approaches to DZ twinning
Dorret Boomsma & Nikki Hubers

Twinning -i.e. a pregnancy resulting in more than one offspring- is widely observed in mammalian species. In humans, dizygotic (DZ) twinning is related to other evolutionary important traits such as fertility and longevity.
Paradoxically, DZ twinning is higher in women who smoke and have higher BMI, traits that otherwise are related to female infertility risk (Hoekstra et al., 2010). To test possible causal pathways, we propose to do a Mendelian Randomization (MR) study (e.g. Sanderson et al.,2022) based on the latest meta-GWAS for DZ twinning (Mbarek et al., 20240) with smoking, BMI and possibly other lifestyle traits.
A more extended Phewas study can be carried out by applying latent causal variants (LCV) methods (see for example: Aman et al., 2022). Both approaches take -published- GWA studies as input.

Aman AM, García-Marín LM, Thorp JG, Campos AI, Cuellar-Partida G, Martin NG, Rentería ME. Phenome-wide screening of the putative causal determinants of depression using genetic data. Hum Mol Genet. 2022;31(17):2887-2898. doi: 10.1093/hmg/ddac081
Hoekstra C, Willemsen G, van Beijsterveldt CE, Lambalk CB, Montgomery GW, Boomsma DI. Body composition, smoking, and spontaneous dizygotic twinning. Fertil Steril. 2010;93(3):885-93. doi:10.1016/j.fertnstert.2008.10.012.
Mbarek H, Gordon SD, Duffy DL, Hubers N, Mortlock S, Beck JJ, Hottenga JJ, Pool R, Dolan CV, Actkins KV, Gerring ZF, Van Dongen J, Ehli EA, Iacono WG, Mcgue M, Chasman DI, Gallagher CS, Schilit SLP, Morton CC, Paré G, Willemsen G, Whiteman DC, Olsen CM, Derom C, Vlietinck R, Gudbjartsson D, Cannon-Albright L, Krapohl E, Plomin R, Magnusson PKE, Pedersen NL, Hysi P, Mangino M, Spector TD, Palviainen T, Milaneschi Y, Penninnx BW, Campos AI, Ong KK, Perry JRB, Lambalk CB, Kaprio J, Ólafsson Í, Duroure K, Revenu C, Rentería ME, Yengo L, Davis L, Derks EM, Medland SE, Stefansson H, Stefansson K, Del Bene F, Reversade B, Montgomery GW, Boomsma DI, Martin NG. Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity. Hum Reprod. 2024, 5;39(1):240-257. doi:10.1093/humrep/dead247.
Sanderson E, Glymour MM, Holmes MV, Kang H, Morrison J, Munafò MR, Palmer T, Schooling CM, Wallace C, Zhao Q, Smith GD. Mendelian randomization. Nat Rev Methods Primers. 2022, 10;2:6. doi: 10.1038/s43586-021-00092-5