Contributions Lind on Eaves

8/10/2019 Contributions Lind on Eaves

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O R I G I N A L R E S E A R C H

The Contributions of Lindon Eaves to Psychiatric Genetics

Kenneth S. Kendler

Michael C. Neale

Received: 19 June 2013 / Accepted: 10 September 2013 / Published online: 25 September 2013

Springer Science+Business Media New York 2013

The contributions of Lindon Eaves to the field of Psychi-

atric Genetics can be best understood from an historicalperspective. Modern psychiatric genetics began in the

Genealogic-Demographic Department of the German

Research Institute for Psychiatry, established by the then

famous German Psychiatrist, Emil Kraepelin, in the years

immediately before the First World War (Zerbin-Rudin and

Kendler 1996). This department was headed by Ernst

Rudin, a young psychiatrist conversant with the then new

and exciting laws of Mendel. Over the subsequent

20 years, with a range of collaborators and visitors

(including most of the leaders of the next generation of

psychiatric genetics throughout Europe, such as Stromgren

and Slater), the Genealogic-Demographic Department

conducted methodologically cutting edge psychiatric

genetics research (Zerbin-Rudin and Kendler 1996).

Working with Weinberg, Rudin and his colleagues con-

ducted a range of family and twin studies that incorporated

key methodological advances, including the use of the

proband correction method (to obtain correct risk figures),

the abridged Weinberg age correction method (to correct

for what we would now call the problem of age dependent

penetrance) and systematic ascertainment methods with

appropriate concern about the clear specification of the

sampling frame. While this story is darkened by laterinvolvement of Rudins department with the rising Nazi

power in Germany in the 1930s, at its inception, psychiatric

genetics in Europe was closely connected with the latest

developments in Statistical Genetics.

However, nothing similar was then underway in the

United States. The early pioneers in psychiatric and

behavioral geneticsespecially Davenport and Rosanoff

were far from the cutting edge. Davenport was an over-

zealous Mendelizerseeing Mendelian traits in all sorts of

behaviors, of which my favorite example is nomadism

aka the wandering impulse (Davenport1915). Rosanoff

conducted the first twin studies of psychiatric illness in the

US, but had a very unsystematic method of ascertainment

that was always certainly substantially biased (Rosanoff

et al. 1934; Rosanoff and Orr1911).

With a notable few exceptions, after the demise of

Rudins institute in the Second World War, psychiatric

genetics parted company from statistical genetics that, over

the course of the twentieth century, became increasingly a

British-dominated discipline. Two schools of statistical

or biometrical genetics emerged over this time in the UK

one based in Edinburgh and the other in Birmingham.

(While the field has seen much dispute about the intellectual

merits of these two schools, we will not here attempt to

adjudicate this question.) The latter was dominated by

Kenneth Mather, perhaps the most prominent of the stu-

dents trained by the great population and statistical genet-

icist, Ronald Fisher. Douglas Falconer was probably the

best known of the statistical geneticists of the Edinburgh

School in part through his widely read and influential book

Introduction to Quantitative Genetics (Falconer1989).

Our story turns now to Washington University St Louis,

where a hard-nosed empirical school of psychiatry was

K. S. Kendler (&)Department of Psychiatry, Department of Human and Molecular

Genetics, Virginia Institute of Psychiatric and Behavioral

Genetics, Virginia Commonwealth University Medical School,

Box 980126, 800 E. Leigh Street, Room 1-123,

Richmond, VA 23298-0126, USA

e-mail: [email protected]

M. C. Neale

Department of Psychiatry, Department of Human and Molecular

Genetics, Virginia Institute of Psychiatric and Behavioral

Genetics, Virginia Commonwealth University School of

Medicine, Richmond, VA, USA

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DOI 10.1007/s10519-013-9614-x


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nurtured by the two key figures of Sam Guze and Eli

Robins. This was the same group that produced the first

operationalized diagnostic criteria for psychiatric disorders

(Feighner et al.1972; Kendler et al.2010). In their attempts

to develop an empirical approach to the validation of

psychiatric diagnoses, Robins and Guze had emphasized

the use of family and genetic studies (Robins and Guze

1970). As the story was related to KSK, at some point inthe late 1960s, they thought it might be a good idea to send

one of their students to learn about genetics. They had the

good fortune to choose Ted Reich, then a psychiatric res-

ident, and they arranged for him to have a fellowship with

the Edinburgh school in the early 1970s. It was at this

point, after a wandering in the desert for some 30 years,

that psychiatric genetics and statistical genetics recon-

nected. Reichs early and influential work on the multiple

threshold model was one of the early fruits of his collab-

oration with colleagues in Edinburgh (Reich et al. 1972).

Lindon was taught in the other British school of

biometrical genetics. His major mentor was John Jinks,who, in turn, was a student of Kenneth Mather. These latter

two also authored an influential text, named Biometrical

Genetics: The Study of Continuous Variation (Mather and

Jinks 1982). So this made Lindon the cultural great-

grandchild of Fisher in the following progression:

Fisher ? Mather ? Jinks ? Eaves. Lindon Eaves had a

series of important early collaborations with the great

British Psychologist, Eysenck, in the 1970s (e.g. Eaves and

Eysenck 1975; Eaves et al. 1977b), prior to his move to

VCU in 1980. I think it is fair to say, however, that his first

major link to the world of psychiatric genetics was through

KSK, beginning with the relocation of KSK to VCU in

1983, largely for the express purpose of working with

Lindon. It is also noteworthy that Lindons academic col-

league, David Fulker, who trained in genetics in Bir-

mingham largely under the direction of John Jinks as well,

followed Lindon to the US, worked at the Institute for

Behavior Genetics at the University of Colorado, and also

made a series of important contributions to the world of

psychiatric genetics. (He also was the PhD mentor of

MCN, making him the cultural nephew of Lindon and

cousin of Andrew Heath and Nick Martintwo of Lin-

dons most prominent PhD students).

So, although a bit oversimplified, the link of the Edin-

burgh school to Psychiatric Genetics began*1970 via Ted

Reich, who was key in founding the influential Wash-

ington University Psychiatric Genetics group. The link

through the Birmingham school was more than a decade

later through Lindon and KSK, and a bit later MCN,

leading to what is now the Virginia Institute for Psychiatric

and Behavioral Genetics.

With this historical background, we now review Lin-

dons contributions to the field of psychiatric genetics in

three inter-related major categories: data collection meth-

ods, conceptualizations and data analytic methods, and his

approach to science.

Data collection

Lets begin this section by reviewing the status of twinstudies of psychiatric disorders circa 19751980. Nearly all

of the published twin studies examined the relatively severe

disorders, especially schizophrenia and manic-depressive

illness. Ascertainment was typically done only through

hospitalization. Sample sizeswere small, typically under100

pairs of twins. Statistical analysis was largely a v2 compar-

ison of concordance rates in monozygotic versus dizygotic

twins. A rare study would examine an environmental

factor such as birth order or birth weight.A few studiesout

of the main streamwere looking at outcomes, especially

crime, using national registries (e.g. Christiansen1970).

Studies were using mailed questionnaires given to largenumbers of twins. The typical goal was to examine medical

traits but sometime psychological variables such as per-

sonality were also measured. Data analysis was typically

limited to one of the range of ad-hoc heritability mea-

sures then popular such as Holzingers H (Cederlof et al.

1961; Cederlof1966).

Family studies of psychiatric illness were somewhat

more sophisticated. The concept of an ascertainment frame

was generally well understood as were issues of how to

sample controls. But data analysis was largely limited to

statistical comparisons of prevalence rates in relatives of

index vs. control probands, typically with the calculation of

a relative risk statistic (Gershon et al. 1982; Tsuang et al.

1980; Weissman et al.1982; Winokur et al. 1972).

Shortly after KSKs arrival at VCU in 1983, working

closely with Lindon, Andrew Heath and Nick Martin,

together we developed a new paradigm for psychiatric twin

studies. It had the following five key features:

1. Population based sampling.

2. Structured psychiatric interviews.

3. Careful attention to measurement of environmental

risk factors.

4. Required sample size determined by powercalculations.

5. Analysis by structural equation models based on the

Birmingham school quantitative genetic theory.

Population-based sampling was based on concerns about

ascertainment bias from examining treated samples and the

desire to avoid having to assume a population prevalence

for model fitting. No cell would be missing as was the case

in prior twin studies that began with affected individuals

usually from hospitalized setting.

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It was KSKs background in clinical and epidemiolog-

ical research that called for the inclusion of structured

psychiatric interviews rather than a reliance on question-

naire data. Such interviews were necessary if we wanted to

study psychiatric disorders (rather than traits like person-

ality) in a way that would be accepted as valid by the

psychiatric community.

As will be clear later, Lindon had been very interested inthe problems and challenges of jointly modeling genetic

and environmental risk factors. From a clinical perspective,

KSK was interested in similar questions and we had the

wisdom to invite Ron Kessler to join our collaboration, and

he taught us all a lot about how to measure environmental

risk factors as accurately as possible in epidemiological

samples.

Another critical element of this new paradigm was the

addition of power analyses. Now that we had a conceptual

framework (see below), we could clearly articulate prior

hypotheses and then test them using the framework pre-

viously developed by Lindon and Nick (Martin et al. 1978)[and later substantially expanded by the authors, along with

Lindon (Neale et al. 1994)].

KSK clearly recalls the results of their first power cal-

culations done probably in 1984. We were trying to figure

out the sample needed to reject an AE model for major

depression given good guesses for the prevalence and

heritability with 80 % power. Andrew Heath came in with

output in-hand and announced that the needed sample was

around 1,000 pairs. A hush fell on the room. Lindon, Nick

and I (KSK) looked at each other. A thousand pairs! It

seemed like an impossible goal. Little did we know then

that we would write and get funded a grant to study just

such a sample of femalefemale twin pairs across two

waves, and manage to pull it off. We had to create the

study infra-structure from scratch although we had the

invaluable help of the Virginia Twin Registry, established

by Walter Nance and then run by Linda Corey. A few years

later, quite a bit more confident about our ability to study

large samples, we wrote a grant to study over 3,000 pairs

(of malemale and malefemale pairs) over two waves and

got that funded, and met our data collection goals.

Lindon played a central role in the development of this

new data collection paradigm that has fueled many

advances in the field of psychiatric genetic epidemiology.

The final and most important contribution he made to these

studies was that they were to be analyzed using the con-

ceptual framework of the Birmingham school of biomet-

rical genetics in which Lindon had been schooled. While

this method was developed solely on well behaved model

organisms like Nicotinia rustica and Drosophila, it was

Lindons major contribution to apply these methods to

humans. To paraphrase a remark made long ago by Lindon,

we knew that studying humans was much harder than

tractable experimental organisms which largely stayed put

and where one could control both their genes (by breeding)

and their environment. But, he would say, with his wry

smile, that means you just have to be that much smarter in

your data collection and analytic approach.

As we will comment below, Lindon also played a

seminal role in other data collection efforts that substan-

tially influenced the field, especially the use of a range oftwin-family and longitudinal developmental designs.

Conceptual contributions

It will be difficult to convey to current readers what psy-

chiatric genetics research was like in the early 1980s (with

the notable exception of a few folks at Washington Uni-

versity St Louis, and at Yale University). Ideas that we

currently take for grantedthat we could form precise

statistical/conceptual models of familial transmission, andthen test the fit of these models to observed datawere

unknown. We understood that you could measure familial

aggregation (e.g. by relative risk statistics) or twin simi-

larity by concordance, and had some rough idea that you

might learn something about the role of genes by com-

paring concordance rates in MZ versus DZ twins, but that

was about it.

The corpus of model fitting techniques that Lindon was

critical in importing into psychiatric genetics research

(along with parallel methods brought back from Edinburgh

by Ted Reich) were transformative. One of us, KSK, still

clearly remembers the early phases of his first detailedmodeling fitting paper (Kendler et al.1986). It seemed little

short of miraculous that you could postulate a specific set

of causes for variance in the liability to (in this case)

symptoms and then systematically test which of these

models provided the best overall explanation of the data.

And even better, these models were based on well-under-

stood genetic and evolutionary principles. They were not

ad-hoc. These methods cast the nature of the underlying

inquiry in an entirely different light.

So the method was important. It carried with it a deeper

structurea clear road from hypothesis testing (based, in

turn, on animal genetics and evolutionary theory about themechanisms of familial resemblance) to hypothesis evalu-

ation. It reflected a scientific method applied to a field that

was heretofore largely descriptive. Lindons approach to

human behavior genetics could be succinctly described as

elegant and rigorous. This spirit is well captured in the

following quote from one of Lindons major early papers

(Eaves et al.1978, p. 251):

Whatever the shortcomings of present data, there is

no substitute for a model fitting approach which tries

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to predict the findings for multiple biological and

non-biological relationships from a consistent and

parsimonious theory The fundamental position is

not any desire to see genetical theory vindicated in

the behavioral domain but the conviction that any

theory of individual differences must be quantitative

to be testable.

Importantly, Lindon also repeatedly emphasized the

importance of moving beyond the ideological controversies

that swirled around the field of behavior genetics in the

1970s. As he wrote eloquently, the empirical questions

about the relative importance of nature and nurture, and

their interrelationship should be decided on the basis of

data and not on philosophy, politics or prejudice. (Eaves

et al. 1978, p. 315).

Equally important to this more abstract conceptual

influence was Lindons sketching out the paradigm

spacethe sets of questions that he foresaw that were to

form the basis of the key inquiries of behavior genetics(seeking to understand the sources of individual differences

on normative traits) and psychiatric genetics (to do the

same for dysfunctional traits or disorders). This was largely

done in two key papers Lindon published in 1977 (Eaves

1977) and 1978 (Eaves et al. 1978). For want of space,

what we can best do here is to give a selected set of issues

that Lindon addressed in these papers which were later

taken up by the field and, as predicted, found to be fertile

sources of insights. But it is only a bit of an exaggeration to

say that much of the research agenda of psychiatric genetic

epidemiology for the subsequent 30 years was outlined in

nascent form in these early essays.

Problems of measurement

From these early writings, Lindon was quite sensitive to the

inevitable intertwining of genetic modeling and measure-

ment issues. If you get the measurement piece seriously

wrong, you may get the wrong answer about sources of

individual differences. It has taken a long time and much

work for the field of psychiatric genetics to begin to catch-

up to this central insight. For the key psychiatric document

of DSM-5, that process has only begun.

Multivariate analysis

Nick Martin and Lindon wrote the key paper here (Martin

and Eaves1977). This method has been important in psy-

chiatric genetics as an approach to the analysis of comor-

bidity and has had substantial influence on current thinking

in nosology. A few examples would include: (i) evidence

that major depression (MD) and generalized anxiety dis-

order (GAD) appear to share the same genetic risk factors;

(ii) evidence of a shared genetic vulnerability across the

phobias; (iii) lack of much specific genetic risk for indi-

vidual substances of abuse; (iv) evidence for broad genetic

risk dimensions for internalizing and externalizing disor-

ders; and (v) more recent evidence that diagnostic criteria

for MD, alcohol dependence, antisocial personality disor-

der, and conduct disorder do not form homogenous genetic

factors.

Longitudinal models

Lindon examined this several times at varying levels of

complexity in his career using quantitative psychological

traits such as personality (Eaves and Young 1981) and IQ

(Eaves et al.1986) with early results, for example, showing

that most E is occasion specific and most A is stable. This

turns out to be largely correct for psychiatric phenotypes.

His work anticipated a whole series of developmental twin

studies of psychiatric symptoms and disorders that have

richly informed the field, and shown that genetic andenvironmental risk factors for psychiatric disorders

undergo both quantitative and qualitative changes over

time. These results have been important in demonstrating

the highly dynamic nature of the genetic and environmental

influences on psychiatric illness. This field has also

strongly influenced data collection strategies with increas-

ing emphasis on samples that are both longitudinal and

genetically informative. He played a key role in one of the

major developmental twin studies conducted over the last

several decades: The Virginia Twin Study of Adolescent

Behavioral Development (Eaves et al. 1997).

Sex effects

As Lindon noted in one of his key early reviews (Eaves

et al. 1978, p. 262), Most analyses of twin data assume

that a score on a given test reflects the same underlying

causes in both sexes. Of course this assumption may be

false and if opposite sex twin pairs are studied quite test-

able. Given the strong impact of sex on prevalence rates for

most psychiatric disorders, these models continue to be

underutilized in psychiatric genetics. However, qualitative

sex effects have been found for both major depression and

alcohol dependence and, at least for MD, these findings

have influenced molecular genetic strategies.

Gene environment covariance and interaction

In his early writings, Lindon was clearly aware of the

potential importance of these processes for human behav-

ioral traits (Eaves et al. 1977a, 1978). He was fond of

quoting the idea that humans were a brain with feet that

could select out environments based in part on genetic

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factors. While increasingly known in the fields of genetics

and psychology, KSK participated with Lindon in a

coming out 1986 article bringing the potential impor-

tance of these two phenomena to the psychiatric research

and clinical communities (Kendler and Eaves 1986). GE

covariance has proven a robust phenomenon and a poten-

tially important part of etiologic pathways from genetic to

psychiatric disorders. Two prominent paths appear to be:

1. Genetic risk for MD ? stressful life events and low

social support ? MD (Kendler et al. 2002).

2. Genetic risk for externalizing traits ? deviant peers,

easy drug access etc.? Drug or alcohol abuse/

dependence (Kendler et al. 2011).

This is not the place to review the explosion of research

in gene environment interactions in psychiatry over the last

decade, and the associated substantive and methodological

controversies except to note Lindons pointed contributions

thereto (Eaves2006; Risch et al. 2009).

Other active areas of psychiatric genetics research

anticipated by Lindon

More briefly, Lindon (and Andrew Heath under his men-

torship) carefully examined assortative mating and its

expected impact on the sources of individual differences

(Maes et al. 1998). Twin family designsappreciated in

several of Lindons early writingshave been used

increasingly for psychiatric and substance use disorders.

Lindon played a key role in creating the Virginia 30,000

sample that first showed the important strengths of the

extended twin design and this approach has been used for a

range of psychiatric traits (Kendler et al.1994; Truett et al.

1994). Lindon also played an important role in further

developing analytic approaches to the twin-offspring

design initially advocated by Corey and Nance (Corey and

Nance 1978). With Judy Silberg, a number of elegant

studies have been emerging using this design to clarify the

sources of parent-offspring resemblance for psychiatric

disorders (e.g. Silberg et al. 2012). Plans are underway to

utilize half-sibling and cousin designs using the population

and other registers in Sweden.

Lindons approach to science

Lindon largely inspired the field of psychiatric genetics

through the force of his ideas. But the way he did science

also was important. We would emphasize three of his traits.

The first was his scholarliness. Lindon read widely and

thought deeply. He knew a lot about basic statistical

genetics and evolutionary theory (not to mention obscure

aspects of Christian theology). When he would say some-

thing like I must be thick here, but we all knew to

hold tight for the coming insightful and sometimes pain-

fully penetrating questions. The second would be his

enthusiasm. Lindons excitement about the science was

infectious. Those of us who knew him well knew that there

was something sparkling about being around him. It was

plain exciting to see him think through problems andinteract with him. The third trait worthy of emphasis was

his generosity. Lindon was the absolute opposite of the

narrow career-focused academic, keeping ideas close to his

chest to get his high profile publications first. He had a

deeply held openness of spirit, a sense of being part of a

broader community dedicated to unselfish inquiry. These

attributes made him a truly exceptional teacher, one who

would lead students (or faculty) through a problem with a

set of questions designed to culminate in aha moments of

insight in the members of the audience. It is difficult to

overstate the value of this approach, since it teaches the

student to think instead of presenting them with pre-pro-cessed knowledge. Quite frequently, Lindon would have

freshly generated this knowledge on the spot, stimulated by

the scientific issues at hand. To witness its creation and

communication to others via Socratic method, madeand

continues to makeVIPBG seminars, thesis defenses, and

other academic meetings a true pleasure.

Consistent with his generative nature and great natural

ability, Lindon established the Behavioral Genetics group

at VCU in the early 1980s, with stellar trainees and col-

leagues, including Nick Martin, Andrew Heath, John He-

witt, Greg Carey, Joanne Meyer, and others. This group

grew during the late 1980s and early 1990s to include a

larger set of students and additional staff to manage the

twin registry and project administration, and relocated to

the old city hall [http://en.wikipedia.org/wiki/Old_City_

Hall_(Richmond,_Virginia)]. The period saw a flurry of

data collection and methodological advances, many of the

fruits of which are discussed elsewhere in this issue. In the

early 1990s, the psychiatric genetics group of KSK also

expanded, hosting faculty such as Drs. Charles MacLean

and Pak Sham. These parallel developments led to the

formation of the Virginia Institute for Psychiatric and

Behavioral Genetics in 1996. Its custom-designed space

(architect, Hermine Maes), originally 17,000 square feet in

the Biotechnology Park, has recently been expanded with

additional molecular laboratories. The Institutes 23 faculty

hold 43 federally-funded research grants and 8 grants

funded by non-federal agencies, and we hope it will con-

tinue to thrive for many intellectual generations to come. It

is worth noting the debt that the Instituteand with it

psychiatric geneticsowes to Dr. Eaves for his leadership

and didactic efforts which were the foundations of its

current success.

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Conclusion

The face of psychiatric genetic epidemiology has been

transformed from circa 1975 to circa 2010. It has gone

from a crudely empirical discipline that quantified familial

resemblance to a model based science which has tried to

clarify an increasingly complex series of latent causal

mechanisms. As in all historical changes in science, thisprocess has been multi-determined. Yet, we would argue

that future historians of this era will see Lindon Eaves as a

seminal figure in this transformation, sharing this acclaim

with a few other key individuals (among them most

prominently his close colleague, David Fulker, and key

figures from the Washington University school of Ted

Reich and Bob Cloninger). It is our perhaps prejudiced

view that Lindon was ultimately the most visionary and

influential of this group of transformative figures.

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