Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved “open consent” process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain—we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.

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Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.The molecular dissection of 'model' disorders is crucial to the elucidation of complex patterns of inheritance, which have been difficult to assess by other means 1-3 . HSCR is a neurocristopathy characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract 4 . The phenotype usually occurs in isolation and is classified by extent of aganglionosis into long-segment (L-HSCR, 20% of affected individuals) and short-segment (S-HSCR, 80%) forms, each with distinct genetic characteristics 5 . HSCR is hereditary but nonmendelian with risk varying by gender, segment length and co-occurrence of non-enteric phenotypes 6 . We have previously concluded that RET is the major gene involved in HSCR, for several reasons: (i) only one affected family unlinked to RET has been reported 7 ; (ii) coding sequence mutations occur in 50% of familial and 15−35% of sporadic cases 8 ; (iii) even when the major mutation is in EDNRB, RET variants make some contribution to susceptibility 9 and (iv) homozygous Ret-null mice have full sex-independent penetrance of aganglinonosis 10 . Yet, RET mutations may not be sufficient to lead to aganglionosis, as the penetrance of mutant alleles is 65% in males and 45% in females 8 . RET is the major gene underlying HSCR primarily in families enriched for L-HSCR 5 . The genes critical for the complex inheritance of the much more common S-HSCR remain unknown.We carried out a genome search of the number and locations of genes conferring susceptibility to S-HSCR in 49 affected families ascertained through a proband with S-HSCR, using 371 tandem repeat polymorphisms at a map resolution of approximately 10 cM. With an incidence of 1 in 6,250 livebirths and a sibling recurrence risk of 3% (ref. 5), the risk ratio (λ) for S-HSCR is 187.5, which allowed us to identify the major segregating risk factors 6 . Consequently, we could both impute or refute the role of all known candidate genes (see Methods), independently assess the role of RET and identify new genes invol...