1. AltshulerD, DalyMJ, LanderES (2008) Genetic mapping in human disease. Science 322: 881–888.
2. StrangerBE, StahlEA, RajT (2011) Progress and promise of genome-wide association studies for human complex trait genetics. Genetics 187: 367–383.
3. ManolioTA, CollinsFS, CoxNJ, GoldsteinDB, HindorffLA, et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.
4. GibsonG (2012) Rare and common variants: Twenty arguments. Nat Rev Genet 13: 135–145.
5. EE, FlintJ, GibsonG, KongA, LealSM, et al. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11: 446–450.
6. NgSB, TurnerEH, RobertsonPD, FlygareSD, BighamAW, et al. (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461: 272–276.
7. ShendureJ, JiH (2008) Next-generation DNA sequencing. Nat Biotechnol 26: 1135–1145.
8. WuMC, LeeS, CaiT, LiY, BoehnkeM, et al. (2011) Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 89: 82–93.
9. MadsenBE, BrowningSR (2009) A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 5: e1000384.
10. B, LealSM (2008) Methods for detecting associations with rare variants for common diseases: Application to analysis of sequence data. Am J Hum Genet 83: 311–321.
11. LiB, LealSM (2009) Discovery of rare variants via sequencing: Implications for the design of complex trait association studies. PLoS Genet 5: e1000481.
12. BamshadMJ, NgSB, BighamAW, TaborHK, EmondMJ, et al. (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12: 745–755.
13. BamshadMJ, ShendureJA, ValleD, HamoshA, LupskiJR, et al. (2012) The centers for Mendelian genomics: A new large-scale initiative to identify the genes underlying rare Mendelian conditions. Am J Med Genet A 158A: 1523–1525.
14. NgSB, BighamAW, BuckinghamKJ, HannibalMC, McMillinMJ, et al. (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42: 790–793.
15. NgSB, BuckinghamKJ, LeeC, BighamAW, TaborHK, et al. (2010) Exome sequencing identifies the cause of a Mendelian disorder. Nat Genet 42: 30–35.
16. NgSB, NickersonDA, BamshadMJ, ShendureJ (2010) Massively parallel sequencing and rare disease. Hum Mol Genet 19: R119–24.
17. 1000 Genomes Project Consortium, Durbin RM, Abecasis GR, Altshuler DL, Auton A, et al (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.
18. 1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, et al (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65.
19. CirulliET, GoldsteinDB (2010) Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11: 415–425.
20. GorlovIP, GorlovaOY, SunyaevSR, SpitzMR, AmosCI (2008) Shifting paradigm of association studies: Value of rare single-nucleotide polymorphisms. Am J Hum Genet 82: 100–112.
21. SchorkNJ, MurraySS, FrazerKA, TopolEJ (2009) Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev 19: 212–219.
22. KiezunA, GarimellaK, DoR, StitzielNO, NealeBM, et al. (2012) Exome sequencing and the genetic basis of complex traits. Nat Genet 44: 623–630.
23. HelgasonH, SulemP, DuvvariMR, LuoH, ThorleifssonG, et al. (2013) A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet 45: 1371–1374.
24. SeddonJM, YuY, MillerEC, ReynoldsR, TanPL, et al. (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 45: 1366–1370.
25. ZhanX, LarsonDE, WangC, KoboldtDC, SergeevYV, et al. (2013) Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 45: 1375–1379.
26. HeinzenEL, DepondtC, CavalleriGL, RuzzoEK, WalleyNM, et al. (2012) Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet 91: 293–302.
27. NeedAC, McEvoyJP, GennarelliM, HeinzenEL, GeD, et al. (2012) Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet 91: 303–312.
28. HuntKA, MistryV, BockettNA, AhmadT, BanM, et al. (2013) Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature 498: 232–235.
29. LiuL, SaboA, NealeBM, NagaswamyU, StevensC, et al. (2013) Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLoS Genet 9: e1003443.
30. LohmuellerKE, SparsoT, LiQ, AnderssonE, KorneliussenT, et al. (2013) Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes. Am J Hum Genet 93: 1072–1086.
31. TennessenJA, BighamAW, O'ConnorTD, FuW, KennyEE, et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64–69.
32. NelsonMR, WegmannD, EhmMG, KessnerD, St JeanP, et al. (2012) An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science 337: 100–104.
33. FuW, O'ConnorTD, JunG, KangHM, AbecasisG, et al. (2013) Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493: 216–220.
34. MarthGT, YuF, IndapAR, GarimellaK, GravelS, et al. (2011) The functional spectrum of low-frequency coding variation. Genome Biol 12: R84–2011-12-9-r84.
35. CoventryA, Bull-OttersonLM, LiuX, ClarkAG, MaxwellTJ, et al. (2010) Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat Commun 1: 131.
36. KeinanA, ClarkAG (2012) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336: 740–743.
37. KryukovGV, ShpuntA, StamatoyannopoulosJA, SunyaevSR (2009) Power of deep, all-exon resequencing for discovery of human trait genes. Proc Natl Acad Sci U S A 106: 3871–3876.
38. SimonsYB, TurchinMC, PritchardJK, SellaG (2014) The deleterious mutation load is insensitive to recent population history. Nat Genet 46: 220–224.
39. WrightAF, CarothersAD, PirastuM (1999) Population choice in mapping genes for complex diseases. Nat Genet 23: 397–404.
40. PritchardJK, PrzeworskiM (2001) Linkage disequilibrium in humans: Models and data. Am J Hum Genet 69: 1–14.
41. PeltonenL, PalotieA, LangeK (2000) Use of population isolates for mapping complex traits. Nat Rev Genet 1: 182–190.
42. Service S, DeYoung J, Karayiorgou M, Roos JL, Pretorious H, et al (2006) Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nat Genet 38: 556–560.
43. ArdlieKG, KruglyakL, SeielstadM (2002) Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 3: 299–309.
44. ReichDE, CargillM, BolkS, IrelandJ, SabetiPC, et al. (2001) Linkage disequilibrium in the human genome. Nature 411: 199–204.
45. AkeyJM, EberleMA, RiederMJ, CarlsonCS, ShriverMD, et al. (2004) Population history and natural selection shape patterns of genetic variation in 132 genes. PLoS Biol 2: e286.
46. BoykoAR, WilliamsonSH, IndapAR, DegenhardtJD, HernandezRD, et al. (2008) Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet 4: e1000083.
47. GutenkunstRN, HernandezRD, WilliamsonSH, BustamanteCD (2009) Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data. PLoS Genet 5: e1000695.
48. KeinanA, MullikinJC, PattersonN, ReichD (2007) Measurement of the human allele frequency spectrum demonstrates greater genetic drift in East Asians than in Europeans. Nat Genet 39: 1251–1255.
49. LohmuellerKE, BustamanteCD, ClarkAG (2009) Methods for human demographic inference using haplotype patterns from genomewide single-nucleotide polymorphism data. Genetics 182: 217–231.
50. VoightBF, AdamsAM, FrisseLA, QianY, HudsonRR, et al. (2005) Interrogating multiple aspects of variation in a full resequencing data set to infer human population size changes. Proc Natl Acad Sci U S A 102: 18508–18513.
51. TennessenJA, O'ConnorTD, BamshadMJ, AkeyJM (2011) The promise and limitations of population exomics for human evolution studies. Genome Biol 12: 127.
52. GazaveE, MaL, ChangD, CoventryA, GaoF, et al. (2014) Neutral genomic regions refine models of recent rapid human population growth. Proc Natl Acad Sci U S A 111: 757–762.
53. LohmuellerKE, BustamanteCD, ClarkAG (2010) The effect of recent admixture on inference of ancient human population history. Genetics 185: 611–622.
54. LohmuellerKE, IndapAR, SchmidtS, BoykoAR, HernandezRD, et al. (2008) Proportionally more deleterious genetic variation in European than in African populations. Nature 451: 994–997.
55. SawyerSA, HartlDL (1992) Population genetics of polymorphism and divergence. Genetics 132: 1161–1176.
56. HernandezRD (2008) A flexible forward simulator for populations subject to selection and demography. Bioinformatics 24: 2786–2787.
57. HoggartCJ, Chadeau-HyamM, ClarkTG, LamparielloR, WhittakerJC, et al. (2007) Sequence-level population simulations over large genomic regions. Genetics 177: 1725–1731.
58. ClampM, FryB, KamalM, XieX, CuffJ, et al. (2007) Distinguishing protein-coding and noncoding genes in the human genome. Proc Natl Acad Sci U S A 104: 19428–19433.
59. Eyre-WalkerA (2010) Evolution in health and medicine Sackler Colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proc Natl Acad Sci U S A 107 Suppl 11752–1756.
60. VisscherPM, HillWG, WrayNR (2008) Heritability in the genomics era—concepts and misconceptions. Nat Rev Genet 9: 255–266.
61. YangJ, LeeSH, GoddardME, VisscherPM (2011) GCTA: A tool for genome-wide complex trait analysis. Am J Hum Genet 88: 76–82.
62. ZaitlenN, KraftP (2012) Heritability in the genome-wide association era. Hum Genet 131: 1655–1664.
63. DempsterER, LernerIM (1950) Heritability of threshold characters. Genetics 35: 212–236.
64. RischNJ (2000) Searching for genetic determinants in the new millennium. Nature 405: 847–856.
65. GazaveE, ChangD, ClarkAG, KeinanA (2013) Population growth inflates the per-individual number of deleterious mutations and reduces their mean effect. Genetics 195: 969–978.
66. HaldaneJBS (1937) The effect of variation on fitness. Am Nat 71: 337–349.
67. MullerHJ (1950) Our load of mutations. Am J Hum Genet 2: 111–176.
68. PurcellSM, MoranJL, FromerM, RuderferD, SolovieffN, et al. (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506: 185–190.
69. LangeLA, HuY, ZhangH, XueC, SchmidtEM, et al. (2014) Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet 94: 233–245.
70. WrayNR, PurcellSM, VisscherPM (2011) Synthetic associations created by rare variants do not explain most GWAS results. PLoS Biol 9: e1000579.
71. VisscherPM, BrownMA, McCarthyMI, YangJ (2012) Five years of GWAS discovery. Am J Hum Genet 90: 7–24.
72. PritchardJK (2001) Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 69: 124–137.
73. ThorntonKR, ForanAJ, LongAD (2013) Properties and modeling of GWAS when complex disease risk is due to non-complementing, deleterious mutations in genes of large effect. PLoS Genet 9: e1003258.
74. International Schizophrenia Consortium (2009) PurcellSM, WrayNR, StoneJL, VisscherPM, et al. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460: 748–752.
75. Lango AllenH, EstradaK, LettreG, BerndtSI, WeedonMN, et al. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: 832–838.
76. WilliamsSM, HainesJL (2011) Correcting away the hidden heritability. Ann Hum Genet 75: 348–350.
77. KimuraM, MaruyamaT, CrowJF (1963) The mutation load in small populations. Genetics 48: 1303–1312.
78. RobertsDF, BillewiczWZ, McGregorIA (1978) Heritability of stature in a West African population. Ann Hum Genet 42: 15–24.
79. WrightA, CharlesworthB, RudanI, CarothersA, CampbellH (2003) A polygenic basis for late-onset disease. Trends Genet 19: 97–106.
80. SivakumaranS, AgakovF, TheodoratouE, PrendergastJG, ZgagaL, et al. (2011) Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet 89: 607–618.
81. MaherMC, UricchioLH, TorgersonDG, HernandezRD (2012) Population genetics of rare variants and complex diseases. Hum Hered 74: 118–128.
82. PavardS, MetcalfCJ (2007) Negative selection on BRCA1 susceptibility alleles sheds light on the population genetics of late-onset diseases and aging theory. PLoS One 2: e1206.
83. LymanRF, LawrenceF, NuzhdinSV, MackayTF (1996) Effects of single P-element insertions on bristle number and viability in Drosophila melanogaster. Genetics 143: 277–292.
84. ParkJH, GailMH, WeinbergCR, CarrollRJ, ChungCC, et al. (2011) Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants. Proc Natl Acad Sci U S A 108: 18026–18031.
85. TorgersonDG, BoykoAR, HernandezRD, IndapA, HuX, et al. (2009) Evolutionary processes acting on candidate cis-regulatory regions in humans inferred from patterns of polymorphism and divergence. PLoS Genet 5: e1000592.
86. Agarwala V, Flannick J, Sunyaev S, GoT2D Consortium, Altshuler D (2013) Evaluating empirical bounds on complex disease genetic architecture. Nat Genet 45: 1418–1427.
87. ZukO, SchaffnerSF, SamochaK, DoR, HechterE, et al. (2014) Searching for missing heritability: Designing rare variant association studies. Proc Natl Acad Sci U S A 111: E455–64.
88. DoR, KathiresanS, AbecasisGR (2012) Exome sequencing and complex disease: Practical aspects of rare variant association studies. Hum Mol Genet 21: R1–9.
89. KinnamonDD, HershbergerRE, MartinER (2012) Reconsidering association testing methods using single-variant test statistics as alternatives to pooling tests for sequence data with rare variants. PLoS One 7: e30238.
90. CastoAM, FeldmanMW (2011) Genome-wide association study SNPs in the human genome diversity project populations: Does selection affect unlinked SNPs with shared trait associations? PLoS Genet 7: e1001266.
91. ChenR, CoronaE, SikoraM, DudleyJT, MorganAA, et al. (2012) Type 2 diabetes risk alleles demonstrate extreme directional differentiation among human populations, compared to other diseases. PLoS Genet 8: e1002621.
92. BustamanteCD, BurchardEG, De la VegaFM (2011) Genomics for the world. Nature 475: 163–165.
93. CarlsonCS, MatiseTC, NorthKE, HaimanCA, FesinmeyerMD, et al. (2013) Generalization and dilution of association results from European GWAS in populations of non-European ancestry: The PAGE study. PLoS Biol 11: e1001661.
94. ShrinerD, AdeyemoA, GerryNP, HerbertA, ChenG, et al. (2009) Transferability and fine-mapping of genome-wide associated loci for adult height across human populations. PLoS One 4: e8398.
95. WatersKM, StramDO, HassaneinMT, Le MarchandL, WilkensLR, et al. (2010) Consistent association of type 2 diabetes risk variants found in Europeans in diverse racial and ethnic groups. PLoS Genet 6: e1001078.
96. MarigortaUM, NavarroA (2013) High trans-ethnic replicability of GWAS results implies common causal variants. PLoS Genet 9: e1003566.