Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants.
BACKGROUND
Mendelian Randomization (MR) studies assess the causality of an exposure-disease association using genetic determinants [i.e. instrumental variables (IVs)] of the exposure. Power and IV strength requirements for MR studies using multiple genetic variants have not been explored.


METHODS
We simulated cohort data sets consisting of a normally distributed disease trait, a normally distributed exposure, which affects this trait and a biallelic genetic variant that affects the exposure. We estimated power to detect an effect of exposure on disease for varying allele frequencies, effect sizes and samples sizes (using two-stage least squares regression on 10,000 data sets-Stage 1 is a regression of exposure on the variant. Stage 2 is a regression of disease on the fitted exposure). Similar analyses were conducted using multiple genetic variants (5, 10, 20) as independent or combined IVs. We assessed IV strength using the first-stage F statistic.


RESULTS
Simulations of realistic scenarios indicate that MR studies will require large (n > 1000), often very large (n > 10,000), sample sizes. In many cases, so-called 'weak IV' problems arise when using multiple variants as independent IVs (even with as few as five), resulting in biased effect estimates. Combining genetic factors into fewer IVs results in modest power decreases, but alleviates weak IV problems. Ideal methods for combining genetic factors depend upon knowledge of the genetic architecture underlying the exposure.


CONCLUSIONS
The feasibility of well-powered, unbiased MR studies will depend upon the amount of variance in the exposure that can be explained by known genetic factors and the 'strength' of the IV set derived from these genetic factors.
Pierce
Brandon L
BL
Department of Health Studies, University of Chicago, Chicago, IL, USA. bpierce@health.bsd.uchicago.edu
Ahsan
Habibul
H
Vanderweele
Tyler J
TJ
D015982:Bias; D005240:Feasibility Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D017720:Molecular Epidemiology; D018570:Risk Assessment; D012680:Sensitivity and Specificity
Am J Hum Genet. 2009 Apr;84(4):477-82
19303062
J Clin Invest. 2008 Jul;118(7):2620-8
18521185
Am J Hum Genet. 2009 Feb;84(2):123-33
19185284
Nat Genet. 2008 Apr;40(4):437-42
18327257
Nat Genet. 2009 Jun;41(6):648-50
19448620
Nat Genet. 2009 Jun;41(6):724-8
19448621
Stat Med. 2008 Jul 10;27(15):2745-9
18344186
Am J Hum Genet. 2008 May;82(5):1193-201
18439552
Nat Genet. 2009 Jan;41(1):89-94
19060909
Trends Genet. 2008 Aug;24(8):408-15
18597885
Nat Genet. 2009 Jun;41(6):729-33
19448623
Nat Genet. 2008 Apr;40(4):430-6
18327256
Am J Hum Genet. 2008 Oct;83(4):520-8
18940312
Lancet. 2003 Sep 20;362(9388):930-1
14511923
Blood. 2009 Apr 16;113(16):3831-7
19221038
Stat Methods Med Res. 2007 Aug;16(4):309-30
17715159
Am J Hum Genet. 2008 Jan;82(1):139-49
18179892
Nat Genet. 2009 Jan;41(1):56-65
19060906
Nat Genet. 2009 Jan;41(1):77-81
19060907
Nat Genet. 2008 Oct;40(10):1160-2
18776911
Nat Genet. 2009 Jun;41(6):677-87
19430479
Nat Genet. 2009 Jun;41(6):734-8
19448622
Hum Mol Genet. 2008 Oct 15;17(R2):R143-50
18852203
Am J Epidemiol. 2009 Feb 1;169(3):273-84
19033525
Nat Genet. 2009 Jan;41(1):25-34
19079261
Nat Genet. 2009 Feb;41(2):157-9
19151714
PLoS Genet. 2008 May 09;4(5):e1000072
18464913
Nat Genet. 2009 May;41(5):527-34
19396169
Am J Hum Genet. 2008 May;82(5):1185-92
18439548
Stat Med. 2008 Apr 15;27(8):1133-63
17886233
PLoS Genet. 2007 Nov;3(11):e194
17997608
Nat Genet. 2009 Jan;41(1):35-46
19060910
Lancet. 2005 Dec 3;366(9501):1954-9
16325697
Int J Epidemiol. 2004 Feb;33(1):21-5
15075141
Nat Rev Genet. 2009 Feb;10(2):109-21
19139765
Nat Genet. 2009 Jan;41(1):47-55
19060911
Science. 2008 May 23;320(5879):1085-8
18451265
Am J Hum Genet. 2009 Jan;84(1):66-71
19110211
PLoS Med. 2008 Aug 12;5(8):e155
18700811
Int J Epidemiol. 2008 Oct;37(5):1161-8
18463132
Nat Genet. 2009 Jun;41(6):666-76
19430483
Int J Biostat. 2008;4(1):Article 17
22462152
Lancet. 2008 Dec 6;372(9654):1953-61
18834626
PLoS Genet. 2009 Mar;5(3):e1000420
19282985
Nat Genet. 2009 Jun;41(6):645-7
19448619
Nat Genet. 2009 Jan;41(1):18-24
19079260