The Genetic Landscape of the Human Solute Carrier (SLC) Transporter Superfamily
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Human Genetics (2019) 138:1359–1377 https://doi.org/10.1007/s00439-019-02081-x ORIGINAL INVESTIGATION The genetic landscape of the human solute carrier (SLC) transporter superfamily Lena Schaller1 · Volker M. Lauschke1 Received: 4 August 2019 / Accepted: 26 October 2019 / Published online: 2 November 2019 © The Author(s) 2019 Abstract The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual diferences in drug efcacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identifed, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conserva- tion, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional efects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identifed in a single population. Interestingly, population-specifc carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the eth- nogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specifc prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual diferences in SLC transporter function and guide the optimization of population-specifc genotyping strategies in the bourgeoning felds of personalized medicine and precision public health. Introduction genome with over 400 proteins classifed into 65 subfami- lies based on sequence similarity (Fredriksson et al. 2008; The solute carrier (SLC) gene superfamily is one of two Höglund et al. 2011; Schlessinger et al. 2013). Substrate major human gene families encoding transporters of endog- specifcity difers substantially across the various subfami- enous and exogenous compounds. SLCs constitute the lies. While some subfamilies, such as the carbohydrate and second-largest family of membrane proteins in the human long chain fatty acid transporters of the SLC2 and SLC27 subfamilies, transport only few physicochemically homog- Electronic supplementary material The online version of this enous substrates (Anderson and Stahl 2013; Mueckler and article (https ://doi.org/10.1007/s0043 9-019-02081 -x) contains Thorens 2013), transporters of the SLC22 family mediate the supplementary material, which is available to authorized users. translocation of various dissimilar ions, including organic cations, anions, and zwitterions (Koepsell 2013). Most SLC * Volker M. Lauschke [email protected] transporters are equilibrative, making use of electrochemi- cal and concentration gradients to facilitate the uptake of 1 Department of Physiology and Pharmacology, their substrates into cells. Transport mechanisms can difer Section of Pharmacogenetics, Karolinska Institutet, within subfamilies, however, as seen in the secondary active 171 77 Stockholm, Sweden Vol.:(0123456789)1 3 1360 Human Genetics (2019) 138:1359–1377 symporters and antiporters of the SLC4 bicarbonate trans- obtained data set constitutes the most comprehensive analy- porter family (Romero et al. 2013). sis of genetic SLC variability published to date and provides Due to their essential roles in the transport of a plethora valuable insights into inter-individual and inter-ethnic dif- of essential organic and inorganic substrates and the high ferences in transporter function with important implica- number (> 100) of SLC transporters that have been asso- tions for drug disposition, efcacy, and toxicity, as well as ciated with human genetic disorders, SLC transporters are population-specifc prevalence of Mendelian SLC diseases. being increasingly investigated as potential drug targets. One prominent example is the development of blockbuster SGLT2 (encoded by SLC5A2) inhibitors for the treatment of Materials and methods diabetic hyperglycaemia, which was inspired by associations between SLC5A2 mutations and familial renal glucosuria Data collection and annotation (OMIM identifer 233100). Besides their role as drug targets, SLC transporters play fundamental roles in the disposition Genetic variability data of 401 genes comprising the human of numerous drugs, including various chemotherapeutics, SLC superfamily were collected from the Genome Aggrega- antidiabetics, and diuretics. Given the extensive genomic tion Database (gnomAD) version 2.1 (Lek et al. 2016). The coverage and the critical role that SLC transporters play in use of these data did not require separate ethical approval, as mediating drug pharmacokinetics and -dynamics (PK/PD), the data are released under the Fort Lauderdale Agreement. the genetic variability of SLC genes is of considerable inter- In total, we analyzed sequencing data of 141,456 unrelated est for human genetics, as well as for drug discovery and individuals spanning seven worldwide populations (64,603 development programs. Non-Finnish Europeans, 12,562 Finns, 12,487 Africans, In the last decade, seminal studies have contributed sub- 9977 East Asians, 15,308 South Asians, 17,720 Latinos, stantially to our understanding of the link between SLC vari- 5185 Ashkenazi Jews, and 3614 from other populations). ability and drug response. Prominent examples include the Variants with low confdence calls were removed. Rare association between variants in SLC22A1, encoding OCT1, and common genetic SNVs were defned as variants with and pharmacokinetics and response to metformin (Dujic MAF < 1% and MAF ≥ 1%, respectively. Copy-number vari- et al. 2015; Sundelin et al. 2017) and variations in SLC19A1, ants’ (CNVs) data from 59,451 individuals were obtained encoding the reduced folate transporter RFT, with toxicity from the Exome Aggregation Consortium and analyzed as of antifolate metabolites (Bohanec Grabar et al. 2012; Cor- previously described (Santos et al. 2018). Linkage analy- rigan et al. 2014; Lima et al. 2014). However, these stud- sis was performed using LDLink (Machiela and Chanock ies were only powered to detect associations with common 2015). Disease associations for the relevant SLC genes were variations. Importantly, recent population-scale sequencing obtained from the Online Mendelian Inheritance in Man projects revealed that rare variations with minor allele fre- (OMIM) database. Deleterious variants in disease-associated quencies (MAF) < 1% greatly outnumber common variants genes were fltered for benign variants using ClinVar Miner in genes involved in drug absorption, distribution, metabo- (Henrie et al. 2018). lism, and excretion (ADME) (Bush et al. 2016; Kozyra et al. 2017; Wright et al. 2018; Zhou and Lauschke 2018). Rare Computational functionality predictions variations are enriched in variants with functional conse- quences and commonly have increased efect sizes compared Missense variants were analyzed using an array of partly to common variants when analyzed in relation to disease orthogonal algorithms that predict the functional impact of (Ingelman-Sundberg et al. 2018; Manolio et al. 2009). genetic variations based on sequence information, evolution- While the extent and functional importance of rare variants ary conservation, structural considerations, and functional is becoming increasingly appreciated, SLC transporters are genomics data. Specifcally, we used SIFT (Ng and Henikof understudied (César-Razquin et al. 2015) and their genetic 2001), Polyphen-2 (Adzhubei et al. 2010), Likelihood Ratio landscape remains to be systematically analyzed. Tests (Chun and Fay 2009), MutationAssessor (Reva et al. Here, we systematically mapped the genetic variability 2011), FATHMM (Shihab et al. 2012), PROVEAN (Choi of the human SLC transporter superfamily by analyzing et al. 2012), VEST3 (Carter et al. 2013), CADD (Kircher consolidated whole-exome and whole-genome sequencing et al. 2014), DANN (Quang et al. 2015), FATHMM-mkl data (WES and WGS, respectively) from 141,456 individu- (Shihab et al. 2015), MetaSVM (Dong et al. 2015), MetaLR als across seven major populations. We profled the SLC (Dong et al. 2015), and GERP++ (Davydov et al. 2010). genetic variability, its functional consequences, and ethno- We considered all variants that resulted in the gain of a stop geographic