the sequencing of several genomes and the hapmap project , coupled to high - density genotyping technologies and new statistical tools , have made possible the systematic interrogation of the genetic basis of complex traits in humans .
largely consistent with the community 's expectations , the past two years have seen a logarithmically expanding number of genomic regions associated with a broad range of phenotypes ( see   for an updated list ) .
we now know of at least 16 potential susceptibility loci for type 2 diabetes in the human genome , and there are similar or better numbers for other diseases , including type 1 diabetes ( 24 + loci ) and crohn 's disease ( 30 + loci ; see   for examples ) .
similar progress has been made in the identification of genomic regions that influence quantitative traits , such as height , metabolite abundance   and drug response .
these discoveries infuse us with optimism about the potential for understanding the key homeostatic pathways that are causally related to these disorders , which could lead to new drug development and better patient management . at the same time , these studies have presented us with some surprising findings .
most importantly , lost in the collective euphoria of apparently rapid progress is the fact that , some notable exceptions notwithstanding , we are now faced with three major challenges .
firstly , the total sum of disease risk attributed to common variants detected by genome - wide association studies ( gwass ) remains modest , raising a problem analogous to the astrophysicists ' search for ' dark matter ' .
secondly , the overwhelming majority of single nucleotide polymorphisms ( snps ) associated with disease lie in intra- or intergenic regions ; there has been a striking dearth of coding snps . finally , almost none of the association studies have led to the identification of the causal allele(s ) , and thus neither the ' disease - associated ' gene , nor indeed the type of lesion ( gain - of - function , loss - of - function , and so on ) , can be identified unequivocally .
the sheer number of disorders subjected to gwas suggests that these deficiencies are unlikely to be random findings , or to represent idiosyncratic genetic architecture of specific phenotypes .
rather , it is likely that these observations result from biological principles that will require a significant shift in our approach to understand them . the second challenge , that of the modest risk conferred by common variants , is in some ways a minor problem , despite the unwelcome consequence that it potentially hinders , and might even defeat , the utility of high - density genotyping as a prognostic clinical tool .
the fact that the relative risk conferred by most snps associated with crohn 's disease lingers in the 1.2 - 1.5 range ( with the exception of alleles of nod2 , which encodes nucleotide oligomerization domain protein 2 , and il23r , which encodes the interleukin-23 receptor ) does not detract from the establishment of the hypothesis that defective autophagy is part of the cause of this disorder , which has , in turn , enabled the development of mammalian models to study the disease process .
likewise , the association of the same genomic regions with discrete disorders can highlight not only suspected relationships ( rheumatoid arthritis and lupus ) , but also novel and surprising ones ( diabetes and colon cancer ; see   for more details ) .
the first and third challenges mentioned above , those of the genetic ' dark matter ' and allele causality ( coupled to mutational models ) , are more complex and are probably interlinked .
reasonable hypotheses have been put forth that suggest that the failure to detect the majority of the genetic load in complex disease is a reflection of insufficient statistical power , as evidenced by the accelerated locus discovery by meta - analyses . at the same time , evolutionary arguments have been proposed to explain the preferential enrichment of non - coding variants in complex disease .
most prominently , it has been suggested that strong ( often coding ) mutations that have a significant impact on fitness would be more likely to be associated with mendelian disorders , whereas milder alleles that affect spatiotemporal patterns of gene expression are more likely candidates for exerting modest effects in complex disease .
it is reasonable to predict that understanding of the total genetic load in complex disease will be enhanced by higher density genotyping , increased sample size and expanded ethnic diversity , and medical resequencing of risk regions .
importantly , however , none of these tools will unequivocally enable the transition from association to causality .
the sobering reality remains that , despite the hundreds of loci identified , the number of bona fide genes associated with complex disease identified through gwass is modest .
regrettably , a guilty - by - association view has emerged and the definitions of ' locus ' and ' gene ' are becoming dangerously interchangeable .
at best , most arguments for the role of specific genes on conferring susceptibility put forth to date are correlative ; although many will turn out to be correct , this is unlikely to be the ubiquitous truth .
case - control association studies pointed to a region on 10q26 that conferred strong susceptibility to amd , and further work suggested that variation in the promoter region of htra1 , which encodes a multi - functional serine protease , might explain the effect .
however , additional genotyping   and , independently , complete resequencing of the risk haplotype , pointed to a deletion in the 3 ' untranslated region ( utr ) of predicted transcript loc387715 that destabilizes its message , suggesting that loss of that transcript , and not htra1 , drives the susceptibility to amd . unfortunately , the presence of a haplotype that is not associated with amd that carries a premature termination codon in loc387715 confounds that hypothesis as well .
similar questions should be raised about the direct involvement in obesity of the fto gene , given that the associated snp lies in intron 1 of that gene 's transcript . even though the fto protein is now being investigated mechanistically to understand energy regulation
, there is no actual evidence that fto is the gene that underlies the association .
notably , fto , and the neighboring gene ftm ( or rpgrip1l ) , which lies less than 1 kilobase away in a head - to - tail orientation , have been shown to be co - regulated by the transcription factor cutl1 , and at least one of the associated snps maps to a predicted cutl1 binding site , raising the possibility that dysfunction at ftm , not fto , might be the driver of the phenotype .
intriguingly , ftm is mutated in several ciliopathies , which are hallmarked , among other features , by hyperphagia - driven obesity .
there is no doubt that additional , denser genotyping , admixture mapping and deep resequencing will refine current loci and uncover new ones .
however , it is important to consider the relative value of these data without physiologically relevant functional interpretation . in some instances ,
population- and genetic - based arguments can suggest that certain alleles cause certain phenotypes , as has been shown by medical resequencing of candidate genes in patients at the extremes of high - density lipoprotein ( hdl ) and low - density lipoprotein ( ldl ) plasma levels . nonetheless , even in these examples , in vitro assays that tested the functional consequences of the mutations were necessary for the researchers to present compelling arguments . given these observations , it might be prudent to refocus our efforts on how to evaluate the physiological impact of genetic and genomic variation on gene function , because without that ability , the contribution of additional gwass on understanding disease mechanisms will remain limited . given the plethora of in vitro and in vivo tools available to the community
, it should be possible to develop assays that can test directly the effect of gene variation in appropriate cell lines , cell types and animal models ; without such tools , we might be left with an unexplorable catalog of associated snps but gain little wisdom about how to develop diagnostics and therapeutics for complex traits .
amd : age - related macular degeneration ; gwas : genome - wide association study ; snp : single nucleotide polymorphism .
i thank sara katsanis and erica davis for helpful discussion and editing of the manuscript . this work was supported by grants r01hd04260 from the national institute of child health and development , r01dk072301 and r01dk075972 from the national institute of diabetes , digestive , and kidney disorders and p20mh084018 from the national institute of mental health .
 technological and analytical advances have led to an unprecedented catalog of genomic regions associated with a broad range of clinically relevant phenotypes in humans . 
 however , some examples notwithstanding , the causes of the overwhelming majority of genetic diseases remain obscure . 
 more importantly , an emerging lesson from genome - wide association studies is that , in most instances , the resolution necessary for identifying actual genes that underlie the phenotype is limited , as is our ability to develop mechanistic , testable disease models from such studies . 
 these new realities will probably necessitate a paradigm shift in our approach to complex traits , for which the combinatorial application of genomic and functional studies will be necessary to understand the mechanism and pathology of genetic disease . here 
 i will discuss these issues and highlight how additional sequencing and genotyping of ever - increasing cohort sizes without functional interpretation is unlikely to improve our ability to dissect the genetic basis of complex traits . 