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Comparisons of Allele Frequencies

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Copyright 1999 by The Johns Hopkins University School of Hygiene and Public Health

All rights reserved

Printed in U.S.A

Departing from Hardy-Weinberg Proportions

association; bias (epidemiology); case-control studies; chi-square statistic; genes; significance tests

have failed to reproduce these results (9). Metaanalyses on these studies (10, 11) concluded that the

differences between cases and controls could be

explained by variation in the genetic marker allele frequencies among the various ethnic groups, as well as

sampling error. This demonstrates that the choice of

appropriate controls can be difficult (2-4, 6), due to

potential unmeasured confounding factors, such as

ethnic background of cases and controls.

Another potential source of error is the choice of

analytic method. The distribution of genotypes is

often compared between cases and controls by using

Pearson's chi-square statistic for a 2 x G contingency

table, where G is the number of observed genotypes.

This method can have limited power when G is large,

because of the large number of degrees-of-freedom.

Alternatively, the frequencies of K alleles are often

compared by cross-classifying both alleles of each

person according to their case-control status, creating

a 2 x K table. Frequencies are then compared with

Pearson's chi-square statistic. The use of allele frequencies can be more appealing than comparing

genotype frequencies because the sample size is

twice as large (with each person contributing two

alleles) and the degrees-of-freedom are fewer.

However, the validity of Pearson's chi-square statis-

have helped to decipher the genetic basis of many

complex diseases. The case-control design provides an

efficient method for assessing these associations.

Unfortunately, many initial genetic associations found

in case-control studies have been difficult to reproduce. This could be due to reporting bias (1), with the

first publication representing an extreme outlier.

Alternatively, bias in choice of cases or controls (2-4),

choice of genetic markers or genotyping errors (5),

unaccounted confounding factors (6), or improper analytic methods could explain the difficulty in replicating

findings. An example of the difficulty in interpreting

multiple case-control association studies is provided

by the controversy of the association of alcoholism and

the dopamine D2 receptor. The first report (7) documented a large odds ratio of 8.7 {p < 0.001); a second

study by the same group of investigators (8) reported a

reduced odds ratio of 3.7 that was still statistically sigReceived for publication February 17,1998 and accepted for publication August 12, 1998.

Abbreviation: HWE, Hardy-Weinberg Equilibrium.

' Department of Health Sciences Research Mayo Clinic/Mayo

Foundation, Rochester, MN.

2

Department of Medical Genetics, Mayo Clinic/Mayo Foundation,

Rochester, MN.

Reprint requests to Dr. Daniel J. Schaid, Harwick 7, Mayo Clinic,

200 First Street S.W., Rochester, MN 55905.

706

Association studies of genetic markers or candidate genes with disease are often conducted using the

traditional case-control design. Cases and controls are sampled from genetically unrelated subjects, and allele

frequencies compared between cases and controls using Pearson's chi-square statistic. An assumption of this

analysis method is that the two alleles within each subject are statistically independent, at least when no

association exists. This is equivalent to assuming that the frequencies of the genotypes in the general population

comply with Hardy-Weinberg Equilibrium proportions, which may not always be the case. However, deviations

from Hardy-Weinberg Equilibrium can inflate the chance of a false-positive association. These results

demonstrate that when comparing the frequencies of two alleles between cases and controls, the chance of a

false-positive association can be substantially increased if homozygotes for the putative high-risk allele are more

common in the general population than predicted by Hardy-Weinberg Equilibrium. In contrast, Pearson's chisquare statistic can be conservative if the frequency of homozygotes for the high-risk allele is less than that

predicted. A statistically valid method that corrects for deviations from Hardy-Weinberg Equilibrium is presented,

so that the chance of a false-positive association is not greater than the acceptable level. Am J Epidemiol

1999;149:706-11.

Am J Epidemiol

a correct analytic method to account for deviations

from HWE when comparing allele frequencies in casecontrol studies.

STATISTICAL METHODS

between cases and controls. Although Pearson's chisquare statistic is often used to make this comparison,

it is easier to present statistical properties by use of an

equivalent statistic, based on the normal distribution.

Let pd denote the estimated frequency of allele A

among diseased cases, and let pc denote that among

the non-diseased controls, where these estimates are

obtained by simply counting alleles. A statistic to compare pd and pc is

z =

~ Pc)

(i)

here Vis the variance of (pd-pc). If Vis correctly specified, z has an approximate standard normal distribution. When HWE exists, V can be written as

^77 I

^ H W E ~~

(2)

to both cases and controls under the null hypothesis

of no association, and Nd and Nc are the number of

cases and controls, respectively. The allele frequency

p can be estimated by pooling cases and controls.

When there are departures from HWE, V can be

written (17) as

~P)

NonHWE

2Nd +

Wj

(3)

latter variance includes a measure of discrepancy

between the frequency of AA homozygotes and that

predicted by HWE; let 6 denote the discrepancy coefficient, where 6 = (PM - p2). Under the null hypothesis

of no association, the relative frequency PM can be estimated by pooling cases and controls, but it is not clear

if this is the best approach when considering power. As

an alternative to expression 3, one can estimate the

variance of the allele frequency among cases,

=W ~

population to maintain the correct false-positive

(Type-I error) rate.

When sampling nonrelated cases and controls, genotypes are independent among people, but alleles within genotypes may or may not be independent.

Statistical independence of alleles is equivalent to the

genotype frequencies complying with HardyWeinberg Equilibrium (HWE) proportions. For a simple case, consider two alleles, denoted A and B, where

A is thought to be the high-risk allele, and B represents

all other alleles. If p is the population frequency of

allele A, then the HWE proportions for genotypes AA,

AB, and BB are p2, 2p(l - p), and (1 - p)2.

Independence of alleles can be tested by comparing the

observed genotype proportions to those expected when

there is HWE (12). Note that even if the general population is in HWE, the expected marker genotype proportions among diseased cases can deviate from HWE

when a true association exists, and the amount of deviation depends on the genetic mechanism. For example,

if a marker allele is associated with a disease because

of a rare dominant disease susceptibility allele, then

HWE is not expected to hold, yet, for association with

a recessive disease susceptibility allele, HWE may

hold among the cases, but with a marker allele frequency greater than in the general population (13, 14).

Hence, testing for HWE should be performed among

only controls, assuming that the disease is rare in the

population.

Deviations from HWE can be caused by multiple

reasons, such as small population variation (random

genetic drift), and the structure of the population. The

latter may include inbreeding, assortative mating,

stratification, or admixture of different ethnic groups.

If a population is composed of a recent admixture of

different ethnic groups that have different frequencies

of marker alleles, then any trait more frequent in one

of these ethnic groups will be positively associated

with any marker allele that is more frequent in that

group, even if the trait and marker locus are not genetically linked. This type of association is an example of

confounding due to ethnic background. As a method

to assess the potential for an admixed population, it

has been proposed that testing for departures from

HWE should be routinely performed for association

studies (15). However, the impact of departures from

HWE on the Type-I error rate has been ignored in

many applications.

When comparing allele frequencies between cases

and controls, ignoring deviations from HWE can alter

the Type-I error rate. Although this has been speculated to occur (16), the magnitude of the problem has not

been explored. The purposes of this paper are to quan-

707

708

by using only cases to estimate p and PAA' and a similar method for controls to estimate V.NooHWEj:' and then

add these to compute

>

= PI

'NonHWE

= V,NonHWE,*/

+ v,NonHWE,c-

*

= PI

HWb

- P

So,

ZNonHWE

the

^NonHWE> which depends on the discrepancy

coefficient 8, determines the true Type-I error rate. The

effects of departure from HWE on the true Type-I error

rate are considered separately in situations when there

is an excess and a deficit of AA homozygotes.

When there is an excess of AA homozygotes, 8 > 0.

Because PM = p2 + 8 and p = PM + P^/2 imply that

P ^ = 2[p(l -p) - 8] and Pw is bounded by 0 and 1, the

maximum value of Ii is p{\ -p). At this maximum value,

there are no AB heterozygotes, because PM=p and P ^

= 0. An alternative way to express 8 is a fraction,/, of its

maximal discrepancy value: 8 =fp(l - p)- Substituting

this representation into the variance ratio results in

max = 0.17

^ ^

Nominal Error Rate

0.15-

0.01

0.10max = 0.07

0.05 -

0.01

o.o

0.0

02.

0.4

0.8

0.8

1.0

FIGURE 1. True Type-I error rate as a function of fractional maximum discrepancy from Hardy-Weinberg Equilibrium (HWE) when there is an

excess of AA homozygotes and the assumed Type-I error rate is either 0.01 or 0.05.

either inflated or deflated (i.e., conservative) relative

to the assumed error rate. The Type-I error rate will be

inflated when Viram is an underestimate of the true vanance, which occurs when 5 > 0, or, in other words,

when the frequency of AA homozygotes exceeds that

predicted by HWE. In contrast, the Type-I error rate is

deflated when VHWE is greater than VNonHWE, which

occurs when the frequency of AA homozygotes is less

than that predicted by HWE.

To examine the amount of deviation of the true

Type-I error rate from that assumed, let za be the quantile of a standard normal distribution that gives an

assumed Type-I error rate for a two-sided test of a.

Also, let z^^ and zNooHWE be the test statistics using

Vjj^, and VNonHWE, respectively, in expression 1. Note

that if HWE is false, then z^^, does not have a standard

normal distribution, but ztiooHWE does. Assuming HWE

to be false, the Type-I error rate when using zlWfE can

be evaluated by the following probability calculations:

'HWE

(5)

1+/'

'NonHWE

this variance ratio into expression 4 allows evaluation

of the true Type-I error rate.

When a deficiency of AA homozygotes exist, 8 < 0,

and the maximum amount of negative discrepancy is

-p1. At this value, there are no AA homozygotes

because PM = 0 and P^ = 2p. After expressing 5 as a

fraction of its maximum negative value, the variance

ratio can be written as

'HWE

(6)

'NonHWE

RESULTS

that predicted by HWE, the Type-I error rate can be

0.05 -

inflated, as illustrated in figure 1. Here, the true TypeI error rate is plotted as a function of the fractional

maximum discrepancy, for an assumed Type-I error

rate of either 5 percent or 1 percent. When discrepancy

is at its maximum, the true Type-I error rate can be as

high as 17 percent for an assumed rate of 5 percent,

and as high as 7 percent for an assumed rate of 1 percent.

When the frequency of AA homozygotes is less than

that predicted by HWE, the Type-I error rate can be

deflated, as illustrated in figure 2 for both a common

allele (p = 0.25) and a rare allele (p = 0.05). For a common allele (p = 0.25), the Type-I error rate can be quite

conservative, especially if the assumed error rate is 5

percent. The amount of conservatism is less when the

assumed Type-I error rate is small, as for the assumed

error rate of 1 percent in figure 2. As the allele frequency gets smaller, the amount of negative disequilibrium is also reduced, resulting in a less conservative

Type-I error rate (e.g., when p = 0.05 in figure 2).

The results in figures 1 and 2 are based on expression 4, which assumes that the sample size is large

enough for the normal approximation to be adequate.

To validate the adequacy of this approximation, simulations were performed. The genotypes for an equal

number of cases and controls (Nd = Nc = 50 or 100)

were sampled according to the probabilities PM - p2 +

l P /

where p = 0.10 a n d / = 0, 0.5, or 1.0. The maximum

discrepancy, 5 , was p{\ -p) for excess AA homozy-

^

.

p = .O5

0.04 -

0.03 -

LU

%.

0.02 0.01

0.01

_p = .O5

p = .25

0.0

0.0

02

0.4

0.6

0.8

1.0

FIGURE 2. True Type-I error rate as a function of fractional maximum discrepancy from Hardy-Weinberg Equilibrium (HWE) when there is a

deficiency of AA homozygotes, the allele A is either common (p = 0.25) or rare (p = 0.05), and the assumed Type-I error rate is either 0.01 or

0.05.

Am J Epidemiol

In this simple case, only two alleles have been

assumed. Thus, the comparison can focus on only one

allele frequency. When K alleles are compared simultaneously by applying Pearson's chi-square statistic to

&2xK contingency table, this approach can be extended to consider the dependence of alleles under the null

hypothesis.

709

710

TABLE 1. Type-I error rates for statistical methods with and without assumptions of Hardy-Welnberg

Equilibrium (HWE)

Frequency

of

AA

homozygotes

1.0

0.5

0.0

size

(",= " )

Excess

50

100

Large-sample

approximation

0.033

0.047

0.050

0.041

0.057

0.050

0.091

0.104

0.110

0.050

0.062

0.050

0.166

0.147

0.166

0.054

0.049

0.050

Deficient

50

100

Large-sample

approximation

0.040

0.057

0.050

0.050

0.061

0.050

0.054

0.038

0.044

0.052

0.056

0.050

0.028

0.035

0.038

0.050

0.061

0.050

sample size, 1,000 repetitions were sampled; for each

sample, the frequency of allele A was compared

between cases and controls using both z^^ (assuming

HWE) and zNoaHWE (correcting the variance for deviations from HWE), with an assumed Type-I error rate of

5 percent. The simulated Type-I error rates are presented in table 1, along with those predicted by expression 4. For these sample sizes, the simulated Type-I

error rates are close to those predicted, suggesting that

expression 4 is a reliable indicator of the magnitude of

false-positive results when HWE does not hold. Also,

the simulations indicate that zSonHWE adequately corrects for deviations from HWE, achieving the assumed

Type-I error rate of 5 percent.

To illustrate the difference in statistical significance

when considering departures from HWE, both z^^ and

^NMIHWE statistical tests were applied to data recently published on the association of a molecular variant of the

angiotensinogen gene and coronary atherosclerosis. In

the report by Ishigami et al. (18), the molecular variant

of angiotensinogen that exists in exon 2, a thyminecystosine transition at nucleotide 704, was labeled a,

and alleles which did not have this variant were

labeled A. Among the 160 control subjects, 30 had

genotype AA (18.8 percent), 51 had Aa (31.9 percent),

and 79 had aa (49.4 percent). Among the 82 cases with

coronary atherosclerosis, 6 were AA (7.3 percent), 22

were Aa (26.8 percent), and 54 were aa (65.9 percent).

The frequencies of the a allele were 79 percent among

cases and 65 percent among controls, but there was a

significant excess of homozygotes among the controls

(p = 0.00019). In pooled cases and controls, the

amount of departure was 47 percent of the maximum

departure. When ignoring this departure, z^^ = 3.17,

giving a probability value of p = 0.0015. Taking this

0.005. Thus, although both methods of analysis resulted in a statistically significant association for this

example, the strength of significance was less after

appropriately accounting for departures from HWE.

DISCUSSION

HWE can alter the assumed Type-I error rate, and that

the true error rate occurs in a predictable manner. If

AA homozygotes are more common in the general population than predicted by HWE, the chance of a falsepositive finding can be greater than assumed (11 percent if one-half of the maximum discrepancy, and up to

a 17 percent chance, when the assumed chance is 5

percent). Population dynamics that can lead to an

increased frequency of homozygotes are inbreeding, or

a stratified population, also called Wahlund's principle

in population genetics (19).

If homozygotes occur less frequent than predicted

by HWE, the true Type-I error rate will be less than

assumed, leading to a conservative statistical comparison. For a common allele, the amount of conservatism

can be substantial. However, the amount of conservatism depends on the allele frequency, and, as the

candidate allele becomes more rare, the amount of

conservatism becomes smaller. This finding may be

important for associations of alleles that have a selective heterozygote advantage (20).

In summary, these results demonstrate that the probability of a Type-I error can be underestimated when

comparing frequencies of two alleles between cases

and controls when there is a departure from HWE.

Sasieni (16) recently speculated that the Type-I error

rate would not be correct if HWE is falsely assumed.

Am J Epidemiol

Nq, number of cases; Nc, number of controls. Type-I error rates for sample sizes of 50 and 100 are based on

simulations; large sample approximation is based on expression 4 in the text,

t f = 0 implies HWE, and f = 1 is the maximum departure from HWE.

t Zywz, statistic assuming HWE; ztlaltttm, statistic with variance corrections for departure from HWE.

should not be used to compare allele frequencies, but

rather only genotype frequencies should be compared;

trends in genetic relative risks could be assessed with

Armitage's trend test (21). The results presented here

quantify the biased Type-I error rate and demonstrate

how to correctly account for dependencies of alleles

where there are departures from HWE.

7.

8.

9.

10.

11.

ACKNOWLEDGMENTS

12.

GM51256 from the National Institutes of Health.

13.

15.

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3. Wacholder S, Silverman DT, McLaughlin JK, et al. Selection

of controls in case-control studies, n. Types of controls. Am J

Epidemiol 1992;135:1029-41.

4. Wacholder S, Silverman DT, McLaughlin JK, et al. Selection

of controls in case-control studies. HI. Design options. Am J

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5. Stefanski LA, Carroll RJ. Covariate measurement error in

logistic regression. Ann Stat 1985;13:133551.

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Blum K, Nobel EP, Sheridan PJ, et al. Allelic association of

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Gelernter J, Goldman D, Risch N. The Al allele at the D2

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