G C A T T A C G G C A T genes Review The Y Chromosome: A Complex Locus for Genetic Analyses of Complex Human Traits Katherine Parker 1, A. Mesut Erzurumluoglu 2 and Santiago Rodriguez 1,3,* 1 Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK; [email protected] 2 Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge CB2 0SL, UK; [email protected] 3 MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK * Correspondence: [email protected]; Tel.: +44-(0)117-3310133 Received: 9 September 2020; Accepted: 26 October 2020; Published: 29 October 2020 Abstract: The Human Y chromosome (ChrY) has been demonstrated to be a powerful tool for phylogenetics, population genetics, genetic genealogy and forensics. However, the importance of ChrY genetic variation in relation to human complex traits is less clear. In this review, we summarise existing evidence about the inherent complexities of ChrY variation and their use in association studies of human complex traits. We present and discuss the specific particularities of ChrY genetic variation, including Y chromosomal haplogroups, that need to be considered in the design and interpretation of genetic epidemiological studies involving ChrY. Keywords: Y chromosome; Y haplogroups; complex locus; genetic association analyses; genetic epidemiology; complex human traits 1. Introduction During the last decade, genome-wide association studies (GWASs) have identified large numbers of loci associated with common complex human traits, enabling a better understanding of the genetic architecture of human disease [1]. This progress is documented by the NHGRI-EBI GWAS Catalogue [2], which includes all published GWAS hits to date. The latest version (accessed 11/10/20) of the widely used diagram, “SNP-trait associations, mapped onto the human genome by chromosomal location and displayed on the human karyotype”, provided by the catalogue (Figure1), shows evidence of many SNP–trait associations on all 22 autosomes and the X chromosome. Notably, however, none of the GWAS hits found to date reside on the Y chromosome (ChrY). Results from studies of various designs not limited to GWASs (e.g., candidate gene association analyses) also provide evidence that minimises the role of ChrY common genetic variation in relation to human complex traits. It is important to consider alternative explanations for this lack of association, such as the inherent genetic complexity of ChrY, which differs from the remainder of human chromosomes in terms of structure, function and population history. These differences make it more complex to analyse than other human chromosomes, which consequently leads to the removal or misanalysis of ChrY variants from association studies. This review addresses specific features of human ChrY relevant for the design and interpretation of genetic association studies of complex human traits and covers different study designs applied in genetic epidemiological studies of ChrY, discussing their strengths and weaknesses, as well as potential avenues for future research. Genes 2020, 11, 1273; doi:10.3390/genes11111273 www.mdpi.com/journal/genes Genes 2020, 11, 1273 2 of 19 Genes 2020, 11, x FOR PEER REVIEW 2 of 21 FigureFigure 1.1. GWASs can be be used used to to look look for for genetic genetic associ associationsations with with human human disease disease traits traits across across the thehuman human genome. genome. This This figure figure is a ismodified a modified version version of the of GWAS the GWAS diagram diagram from from the September the September 2019 2019version version of the of GWAS the GWAS Catalog, Catalog, a directory a directory which which contains contains more more than than157,000 157,000 associations associations from from4,220 4220publications publications [2]. [The2]. The diagram diagram shows shows hits hits identified identified on on chromosomes chromosomes 22 22 and and X, withwith didifferentfferent categoriescategories of of disease disease indicated indicated by by di differentfferent coloured coloured markers. markers. There There are are no no hits hits which which correspond correspond to to ChrY.ChrY. Legend Legend has has not not been been included included for for clarity, clarity, but but the the original original diagram diagram and and legend legend can can be be found found at at https:https://www.ebi.ac.uk/gwas/diagram.//www.ebi.ac.uk/gwas/diagram. 2.2. TheThe HumanHuman YY Chromosome,Chromosome, a a Complex Complex Locus Locus for for Complex Complex Trait Trait Analysis Analysis SinceSince the the discovery discovery of of ChrY ChrY in in 1921 1921 [3], [3], specific specific particularities particularities related related to its to structure, its structure, function function and populationand population history history have beenhave discovered.been discovered. A comprehensive A comprehensive list can list be can found be found in Table in 1Table. 1. In summary, ChrY is the sex-determining chromosome in humans and is passed strictly from fathersTable to 1.sons.Chronological Current understanding order of the discovery suggests of that the particularitiesthe function of theChrY Y chromosomeis limited with from regards the to complexdiscovery disease of the causal male-determining genes. Here we region provide to exploration a review of of gene the function.literature related to ChrY and complex diseasesYear and also make suggestions for future Description studies. References 1985 ChrY utilised for evolutionary studies ‘genetic distance’ genealogy [4] Table1986 1. Chronological First evidence that order the male-determining of the discovery region of is the located particularities on the short arm of of the the Y chromosomechromosome from [5 ]the discovery1989 of the male-determining ChrY regi polymorphismson to exploration utilised in of phylogenetics gene function. [6] Year1990 First gene, sex-determiningDescription region Y (SRY), mapped onto ChrYReferences [7] 19851990 ChrY utilised Animal models for evolutionary used to investigate studies the influence ‘genetic of ChrY distance’ on hypertension genealogy [8][4] 1991 Sry used in animal models to form transgenic mice [9] First evidence that the male-determining region is located on the short 19861997 ChrY utilised for forensic science and paternity testing [10[5]] arm of the Y chromosome 2000 ChrY utilised for phylogenetics [11] 1989 ChrY polymorphisms utilised in phylogenetics [6] 2000 Association between hind III restriction fragment polymorphism and cardiovascular disease detected [12–15] 1990onwards First gene, sex-determining region Y (SRY), mapped onto ChrY [7] 2002Animal models Y-chromosomalused to investigate haplogroups the established influence of ChrY on [16] 1990 [8] 2003 MSYhypertension first sequenced [17] 2005 1991 UnconvincingSry used evidence in animal relating themodels MSY to to cardiovascular form transgenic disease risk mice is reported [18–21[9]] onwards 19972009 ChrY utilised for forensic science and paternity testing [10] Y haplotypes utilised to investigate association between ChrY and other complex traits [22–24] 2000onwards ChrY utilised for phylogenetics [11] 20002016 Association between Exploration ofhind the functionIII restri of genesction identified fragment on within polymorphism MSY and [25] [12–15] onwards cardiovascular disease detected 2002 Y-chromosomal haplogroups established [16] 2003 MSY first sequenced [17] Genes 2020, 11, 1273 3 of 19 Genes 2020, 11, x FOR PEER REVIEW 3 of 21 In summary, ChrY is the sex-determining chromosome in humans and is passed strictly from 2005 Unconvincing evidence relating the MSY to cardiovascular disease risk fathers to sons. Current understanding suggests that the function of ChrY is limited with[18–21] regards to complexonwards disease causal genes. Here we provideis areported review of the literature related to ChrY and complex 2009 Y haplotypes utilised to investigate association between ChrY and diseases and also make suggestions for future studies. [22–24] onwards other complex traits 2.1. Structure2016 of HumanExploration Chromosome of Ythe and function Recombination of genes identified on within MSY [25] In2.1. mammals, Structure of gender Human is Chromosome dictated by Y and either Recombination the presence or absence of ChrY. This chromosome is structurally unusual in relation to autosomes and, in humans, bears an extremely high quantity of In mammals, gender is dictated by either the presence or absence of ChrY. This chromosome is repetitivestructurally content. unusual ChrY alsoin relation contains to autosomes heterochromatic, and, in humans, X-transposed, bears an X-degenerate, extremely high ampliconic quantity ofand pseudoautosomalrepetitive content. regions ChrY (PAR) also [contains17], formed heterochro over time,matic, as X-transposed, the previously X-deg autologousenerate, ampliconic pair underwent and a sequencepseudoautosomal of large scale regions inversions (PAR) and[17], formed deletion over events time,[ as26 the]. previously autologous pair underwent ChrYa sequence shows of similarity large scale with inversions its counterpart, and deletion the events X chromosome, [26]. at the pseudoautosomal regions present atChrY the telomeres shows similarity (Figure with2). its As counterpart, a result, crossovers the X chromosome, involving at ChrYthe pseudoautosomal can only occur regions at these regions.present The remainderat the telomeres of ChrY (Figure