Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates and and Nominates in Interaction with
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10−81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10−8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.
Vyšlo v časopise:
Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates and and Nominates in Interaction with. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001308
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001308
Souhrn
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10−81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10−8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.
Zdroje
1. MayeuxR
2003 Epidemiology of neurodegeneration. Annu Rev Neurosci 26 81 104
2. FratiglioniL
De RonchiD
Aguero-TorresH
1999 Worldwide prevalence and incidence of dementia. Drugs & Aging 15 365 375
3. GatzM
ReynoldsCA
FratiglioniL
JohanssonB
MortimerJA
2006 Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63 168 174
4. BergemALM
LannfeltL
1997 Apolipoprotein E type epsilon 4 allele, heritability and age at onset in twins with Alzheimer's disease. Clin Genet 52 408 413
5. MeyerJM
BreitnerJCS
1998 Multiple threshold model for the onset of Alzheimer's disease in the NAS-NRC twin panel. Am J Med Genet 81 92 97
6. AkessonHO
1969 A Population Study of Senile and Arteriosclerotic Psychoses. Hum Hered 19 546
7. BreitnerJCS
FolsteinMF
MurphyEA
1986 Familial Aggregation in Alzheimer Dementia .1. a Model for the Age-Dependent Expression of an Autosomal Dominant Gene. J Psychiatr Res 20 31 43
8. MohsRC
BreitnerJCS
SilvermanJM
DavisKL
1987 Alzheimers-Disease - Morbid Risk among 1st-Degree Relatives Approximates 50-Percent by 90 Years of Age. Arch Gen Psychiatry 44 405 408
9. LautenschlagerNT
CupplesLA
RaoVS
AuerbachSA
BeckerR
1996 Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology 46 641 650
10. Van BroeckhovenC
GentheAM
Van den BergheA
HorsthemkeB
BackhovensH
1987 Failure of Familial Alzheimers-Disease to Segregate with the A4-Amyloid Gene in Several European Families. Nature 329 153 155
11. BirdTD
LampeTH
NemensEJ
MinerGW
SumiSM
1988 Familial Alzheimer's disease in american descendants of the Volga Germans: probable genetic founder effect. Ann Neurol 23 25 31
12. St. George-HyslopPH
MyersRH
HainesJL
FarrerLA
TanziRE
1989 Familial Alzheimers-Disease - Progress and Problems. Neurobiol Aging 10 417 425
13. GoateA
Chartier-HarlinMC
MullanM
BrownJ
CrawfordF
1991 Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349 704 706
14. SherringtonR
RogaevEI
LiangY
RogaevaEA
LevesqueG
1995 Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375 754 760
15. Levy-LahadE
WascoW
PoorkajP
RomanoDM
OshimaJ
1995 Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269 973 977
16. CorderEH
SaundersAM
StrittmatterWJ
SchmechelDE
GaskellPC
1993 Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261 921 923
17. CorderEH
SaundersAM
RischNJ
StrittmatterWJ
SchmechelDE
1994 Protective Effect of Apolipoprotein-E Type-2 Allele for Late-Onset Alzheimer-Disease. Nat Genet 7 180 184
18. MyersRH
SchaeferEJ
WilsonPWF
DagostinoR
OrdovasJM
1996 Apolipoprotein E epsilon 4 association with dementia in a population-based study: The Framingham study. Neurology 46 673 677
19. BennettCL
CrawfordF
OsborneA
DiazP
HoyneJ
1995 Evidence that the APOE locus influences rate of disease progression in late-onset familial Alzheimer's-disease but is not causative. Am J Med Genet B Neuropsychiatr Genet 50 1 6
20. SlooterAJC
CrutsM
KalmijnS
HofmanA
BretelerMMB
1998 Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: The Rotterdam study. Arch Neurol 55 964 968
21. DawEW
HeathSC
WijsmanEM
1999 Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer's disease pedigrees. Am J Hum Genet 64 839 851
22. DawEW
PayamiH
NemensEJ
NochlinD
BirdTD
2000 The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 66 196 204
23. Pericak-VanceMA
GrubberJM
BaileyLR
HedgesD
WestS
2000 Identification of Novel Genes in Late-Onset Alzheimer's Disease. Exp Gerontol 35 1343 1352
24. BlackerD
BertramL
SaundersAJ
MoscarilloTJ
AlbertMS
2003 Results of a high-resolution genome screen of 437 Alzheimer's Disease families. Hum Mol Genet 12 23 32
25. FarrerLA
BowirratA
FriedlandRP
WaraskaK
KorczynAD
2003 Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum Mol Genet 12 415 422
26. ScottWK
HauserER
SchmechelDE
Welsh-BohmerKA
SmallGW
2003 Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. Am J Hum Genet 73 1041 1051
27. WijsmanEM
DawEW
YuCE
PayamiH
SteinbartEJ
2004 Evidence for a novel late-onset Alzheimer's disease locus on chromosome 19p13.2. Am J Hum Genet 75 398 409
28. BertramL
HiltunenM
ParkinsonM
IngelssonM
LangeC
2005 Family-based association between Alzheimer's disease and variants in UBQLN1. N Engl J Med 352 884 894
29. RademakersR
CrutsM
SleegersK
DermautB
TheunsJ
2005 Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. Am J Hum Genet 77 643 652
30. HahsDW
McCauleyJL
CrunkAE
McFarlandLL
GaskellPC
2006 A genome-wide linkage analysis of dementia in the Amish. Am J Med Genet B Neuropsychiatr Genet 141B 160 166
31. LeeJH
ChengR
SantanaV
WilliamsonJ
LantiguaR
2006 Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean Hispanics with familial Alzheimer disease. Arch Neurol 63 1591 1598
32. LiY
GrupeA
RowlandC
NowotnyP
KauweJS
2006 DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Hum Mol Genet 15 2560 2568
33. ButlerAW
NgMYM
HamshereML
ForaboscoP
WroeR
2009 Meta-analysis of linkage studies for Alzheimer's disease-A web resource. Neurobiol Aging 30 1037 1047
34. CoonKD
MyersAJ
CraigDW
WebsterJA
PearsonJV
2007 A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry 68 613 618
35. GrupeA
AbrahamR
LiY
RowlandC
HollingworthP
2007 Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Hum Mol Genet 16 865 873
36. ReimanEM
WebsterJA
MyersAJ
HardyJ
DunckleyT
2007 GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron 54 713 720
37. AbrahamR
MoskvinaV
SimsR
HollingworthP
MorganA
2008 A genome-wide association study for late-onset Alzheimer's disease using DNA pooling. BMC Medical Genomics 1 44
38. BertramL
LangeC
MullinK
ParkinsonM
HsiaoM
2008 Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE. Am J Hum Genet 83 623 632
39. BeechamGW
MartinER
LiYJ
SliferMA
GilbertJR
2009 Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease. Am J Hum Genet 84 35 43
40. CarrasquilloMM
ZouFG
PankratzVS
WilcoxSL
MaL
2009 Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat Genet 41 192 198
41. PodusloSE
HuangR
HuangJ
SmithS
2009 Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis. Am J Med Genet B Neuropsychiatr Genet 150B 50 55
42. HaroldD
AbrahamR
HollingworthP
SimsR
GerrishA
2009 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 62 1088 1093
43. LambertJC
HeathS
EvenG
CampionD
SleegersK
2009 Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41 1094 1099
44. SeshadriS
FitzpatrickAL
IkramMA
DeStefanoAL
GudnasonV
2010 Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease. JAMA 303 1832 1840
45. ZhongH
PrenticeRL
2010 Correcting “‘Winner's Curse” in Odds Ratios from Genomewide Association Findings for Major Complex Human Diseases. Genet Epidemiol 34 78 91
46. JarvikGP
LarsonEB
GoddardKAB
SchellenbergGD
WijsmanEM
1996 Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet 58 191 200
47. SlooterAJC
vanDuijnCM
1997 Genetic epidemiology of Alzheimer disease. Epidemiol Rev 19 107 119
48. McCarthyM
KruglyakL
LanderE
1998 Sib-pair collection strategies for complex diseases. Genet Epidemiol 15 317 340
49. McKhannG
DrachmanD
FolsteinM
KatzmanR
PriceD
1984 Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34 939 944
50. PetersenRC
SmithGE
WaringSC
IvnikRJ
TangalosEG
1999 Mild cognitive impairment - Clinical characterization and outcome. Arch Neurol 56 303 308
51. HughesCP
BergL
DanzigerWL
CobenLA
MarginRL
1982 A new clinical scale for the staging of dementia. Br J Psychiatry 140 566 572
52. MirraSS
HeymanA
McKeelD
SumiSM
CrainBJ
1991 The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41 479 486
53. ChudykA
MasiukM
MyslakM
DomanskiL
SienkoJ
2006 Soluble HLA class I molecules exert differentiated influence on renal graft condition. Transplant Proc 38 90 93
54. MyakishevMV
KhripinY
HuS
HamerDH
2001 High-throughput SNP genotyping by allele-specific PCR with universal energy-transfer-labeled primers. Genome Res 11 163 169
55. HawkinsJR
KhripinY
ValdesAM
WeaverTA
2002 Miniaturized sealed-tube allele-specific PCR. Hum Mutat 19 543 553
56. BekrisLM
MillardSP
GallowayNM
VuleticS
AlbersJJ
2008 Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels. J Alzheimers Dis 13 255 266
57. PotkinSG
GuffantiG
LakatosA
TurnerJA
KruggelF
2009 Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer's Disease. PLoS ONE 4 e6501 doi:10.1371/journal.pone.0006501
58. RosesAD
2010 An Inherited Variable Poly-T Repeat Genotype in TOMM40 in Alzheimer Disease. Arch Neurol 67 536 541
59. GöringHHH
OttJ
1997 Relationship estimation in affected rib pair analysis of late-onset diseases. Eur J Hum Genet 5 69 77
60. SunL
WilderK
McPeekMS
2002 Enhanced pedigree error detection. Hum Hered 54 99 110
61. NielsenDM
EhmMG
WeirBS
1998 Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 63 1531 1540
62. Wittke-ThompsonJK
PluzhnikovA
CoxNJ
2005 Rational inferences about departures from Hardy-Weinberg equilibrium. Am J Hum Genet 76 967 986
63. ZouGY
DonnerA
2006 The merits of testing Hardy-Weinberg equilibrium in the analysis of unmatched case-control data: A cautionary note. Ann Hum Genet 70 923 933
64. PriceAL
PattersonNJ
PlengeRM
WeinblattME
ShadickNA
2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
65. PriceAL
ButlerJ
PattersonN
CapelliC
PascaliVL
2008 Discerning the ancestry of European Americans in genetic association studies. PLoS Genet 4 e236 doi:10.1371/journal.pgen.0030236
66. HarveyCB
HolloxEJ
PoulterM
WangY
RossiM
1998 Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism. Ann Hum Genet 62 215 223
67. HolloxEJ
PoulterM
ZvarikM
FerakV
KrauseA
2001 Lactase haplotype diversity in the Old World. Am J Hum Genet 68 160 172
68. ChoiY
WijsmanEM
WeirBS
2009 Case-control Association Testing in the Presence of Unknown Relationships. Genet Epidemiol 35 668 678
69. JacquardA
1972 Genetic Information Given by a Relative. Biometrics 28 1101 1114
70. MilliganBG
2003 Maximum-likelihood estimation of relatedness. Genetics 163 1153 1167
71. BourgainC
HoffjanS
NicolaeR
NewmanD
SteinerL
2003 Novel case-control test in a founder population identifies P-selectin as an atopy-susceptibility locus. Am J Hum Genet 73 612 626
72. PritchardJK
DonnellyP
2001 Case-control studies of association in structured or admixed populations. Theor Popul Biol 60 227 237
73. FarrerLA
CupplesLA
HainesJL
HymanB
KukullWA
1997 Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278 1349 1356
74. DevlinB
RoederK
1999 Genomic control for association studies. Biometrics 55 997 1004
75. ChapmanJM
CooperJD
ToddJA
ClaytonD
2003 Detecting disease associations due to linkage disequilibrium using haplotype tags: A class of tests and the determinants of statistical power. Hum Hered 56 18 31
76. YuCE
SeltmanH
PeskindER
GallowayN
ZhouPX
2007 Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: Patterns of linkage disequilibrium and disease/marker association. Genomics 89 655 665
77. CruchagaC
KauweJSK
MayoK
SpiegelN
BertelsenS
2010 SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease. PLoS Genet 6 e1001101 doi:10.1371/journal.pgen.1001101
78. TangMX
SternY
MarderK
BellK
GurlandB
1998 The APOE-epsilon 4 allele and the risk of Alzheimer disease among African Americans, Whites, and Hispanics. JAMA 279 751 755
79. RomasSN
SantanaV
WilliamsonJ
CiappaA
LeeJH
2002 Familial Alzheimer disease among Caribbean Hispanics - A reexamination of its association with APOE. Arch Neurol 59 87 91
80. RosenbergNA
VanLiereJM
2009 Replication of Genetic Associations as Pseudoreplication due to Shared Genealogy. Genet Epidemiol 33 479 487
81. HeathSC
GutIG
BrennanP
McKayJD
BenckoV
2008 Investigation of the fine structure of European populations with applications to disease association studies. Eur J Hum Genet 16 1413 1429
82. LucotteG
LoiratF
HazoutS
1997 Pattern of gradient of apolipoprotein E allele *4 frequencies in Western Europe. Hum Biol 69 253 262
83. CorboRM
ScacchiR
1999 Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? Ann Hum Genet 63 301 310
84. SinghPP
SinghM
MastanaSS
2006 APOE distribution in world populations with new data from India and the UK. Ann Hum Biol 33 279 308
85. RosenmannH
MeinerZ
KahanaE
AladjemZ
FriedmanG
2003 An association study of the codon 72 polymorphism in the pro-apoptotic gene p53 and Alzheimer's disease. Neurosci Lett 340 29 32
86. Dresner-PollakR
KinnarT
FriedlanderY
SharonN
RosenmannH
2009 Estrogen Receptor Beta Gene Variant Is Associated with Vascular Dementia in Elderly Women. Genet Test Mol Biomarkers 13 339 342
87. LittleJ
HigginsJPT
IoannidisJPA
MoherD
GagnonF
2009 Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement. Hum Genet 125 131 151
88. NelisM
EskoT
MagiR
ZimprichF
ZimprichA
2009 Genetic Structure of Europeans: A View from the North-East. PLoS ONE 4 e5472 doi:10.1371/journal.pone.0005472
89. ZekraouiL
LagardeJP
RaisonnierA
GerardN
AouizerateA
1997 High frequency of the apolipoprotein E *4 allele in African pygmies and most of the African populations in sub-Saharan Africa. Hum Biol 69 575 581
90. VoightBF
PritchardJK
2005 Confounding from cryptic relatedness in case-control association studies. PLoS Genet 1 e32 doi:10.1371/journal.pgen.0010032
91. BhattacharjeeS
WangZ
CiampaJ
KraftP
ChanockS
2010 Using Principal Components of Genetic Variation for Robust and Powerful Detection of Gene-Gene Interactions in Case-Control and Case-Only Studies. Am J Hum Genet 86 331 342
92. BlackerD
BertramL
SaundersAJ
MoscarilloTJ
AlbertMS
2001 Results of a high resolution genome screen in 443 Alzheimer's disease families: the NIMH Genetics Initiative. Am J Hum Genet 69 498 498
93. LeeJH
ChengR
Graff-RadfordN
ForoudT
MayeuxR
2008 Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study Implication of Additional Loci. Arch Neurol 65 1518 1526
94. PastorP
RoeC
VillegasA
BedoyaG
ChakravertyS
2003 Apolipoprotein E ε4 modifies Alzheimer's disease onset in an E280A PS1 Kindred. Ann Neurol 54 163 169
95. WijsmanEM
DawEW
YuX
SteinbartEJ
NochlinD
2005 APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation. Am J Med Genet B Neuropsychiatr Genet 132B 14 20
96. MarchaniEE
BirdTD
SteinbartEJ
RosenthalE
YuCE
2010 Evidence for three loci modifying age-at-onset of Alzheimer's disease in early-onset PSEN2 families. Am J Med Genet B Neuropsychiatr Genet 153B 1031 1041
97. PaciniA
ToscanoA
CesatiV
CozziA
MeliE
2005 NAPOR-3 RNA binding protein is required for apoptosis in hippocampus. Brain Res Mol Brain Res 140 34 44
98. FalkevallA
AlikhaniN
BhushanS
PavlovPF
BuschK
2006 Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem 281 29096 29104
99. JunG
NajAC
BeechamGW
WangLS
BurosJ
2010 Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol Sept. 3 Epub ahead of print
100. CarrasquilloMM
BelbinO
HunterTA
MaL
BisceglioGD
2010 Replication of CLU, CR1, and PICALM Associations With Alzheimer Disease. Arch Neurol 67 961 964
101. WakefieldJ
2009 Bayes Factors for Genome-Wide Association Studies: Comparison with P-values. Genet Epidemiol 33 79 86
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 2
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci
- MiRNA Control of Vegetative Phase Change in Trees
- The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MicroRNAs
- Break to Make a Connection