Exploring the unknown: assumptions about allelic architecture and strategies for susceptibility variant discovery

Identification of common-variant associations for many common disorders has been highly effective, but the loci detected so far typically explain only a small proportion of the genetic predisposition to disease. Extending explained genetic variance is one of the major near-term goals of human genetic research. Next-generation sequencing technologies offer great promise, but optimal strategies for their deployment remain uncertain, not least because we lack a clear view of the characteristics of the variants being sought. Here, I discuss what can and cannot be inferred about complex trait disease architecture from the information currently available and review the implications for future research strategies.

[1]  Subhajyoti De,et al.  Common variants near MC4R are associated with fat mass, weight and risk of obesity , 2008, Nature Genetics.

[2]  D. Goldstein.  Common genetic variation and human traits. , 2009, The New England journal of medicine.

[3]  W. Bodmer,et al.  Common and rare variants in multifactorial susceptibility to common diseases , 2008, Nature Genetics.

[4]  B. Maher.  Personal genomes: The case of the missing heritability , 2008, Nature.

[5]  M. Kanai,et al.  Rare Variants of IFIH 1 , a Gene Implicated in Antiviral Responses , Protect Against Type 1 Diabetes , 2009 .

[6]  Robert T. Schultz,et al.  Common genetic variants on 5p14.1 associate with autism spectrum disorders , 2009, Nature.

[7]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[8]  Helen Schuilenburg,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[9]  E. Nimmo,et al.  Molecular genetics of Crohn's disease. , 2004, Current opinion in genetics & development.

[10]  John K. Gohagan,et al.  The prostate, lung, colorectal and ovarian (PLCO) cancer screening trial , 2000 .

[11]  W. G. Hill,et al.  Heritability in the genomics era — concepts and misconceptions , 2008, Nature Reviews Genetics.

[12]  K. Frazer,et al.  Common vs. rare allele hypotheses for complex diseases. , 2009, Current opinion in genetics & development.

[13]  Thomas W. Mühleisen,et al.  Large recurrent microdeletions associated with schizophrenia , 2008, Nature.

[14]  David M. Evans,et al.  Genome-wide association analysis identifies 20 loci that influence adult height , 2008, Nature Genetics.

[15]  Mark I McCarthy,et al.  Learning From Molecular Genetics , 2008, Diabetes.

[16]  John L Hopper,et al.  Multiple loci with different cancer specificities within the 8q24 gene desert. , 2008, Journal of the National Cancer Institute.

[17]  J. Gohagan,et al.  The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. , 2000, Controlled clinical trials.

[18]  H. Shin,et al.  Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians , 2008, Diabetes.

[19]  P. Visscher,et al.  Rare chromosomal deletions and duplications increase risk of schizophrenia , 2008, Nature.

[20]  P. Doris.  Hypertension Genetics, Single Nucleotide Polymorphisms, and the Common Disease:Common Variant Hypothesis , 2002, Hypertension.

[21]  J. Hirschhorn.  Genomewide association studies--illuminating biologic pathways. , 2009, The New England journal of medicine.

[22]  Sarah L. Brown,et al.  A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells , 2008, Nature.

[23]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[24]  J. Todd,et al.  Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes , 2009, Science.

[25]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[26]  D. Clayton,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[27]  W. G. Hill,et al.  Data and Theory Point to Mainly Additive Genetic Variance for Complex Traits , 2008, PLoS genetics.