Genetic Studies of Autism: From the 1970s into the Millennium

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Journal of Abnormal Child Psychology PL114-45 February 2, 2000 15:53 Style file version June 09, 1999

Journal of Abnormal Child Psychology, Vol. 28, No. 1, 2000, pp. 3–14

Genetic Studies of Autism: From the 1970sinto the Millennium

Michael Rutter1

Received July 26, 1999; revision received August 20, 1999; accepted August 20, 1999

Reviewers in the 1960s and early 1970s were skeptical about any substantial role for genetic factorsin the etiology of autism. A realization that the 2% rate of autism in siblings (as estimated at thattime) was far above the general population base rate, and that this suggested a possible high geneticliability, led to the first small-scale twin study of autism. The replicated evidence from both twinand family studies undertaken in the 1970s and 1980s indicated both strong genetic influences andthe likelihood that they applied to a phenotype that was much broader than the traditional diagnosticcategory of autism. Medical and chromosomal findings also indicated genetic heterogeneity. Advancesin molecular genetics led to genome-wide scans of affected relative pair samples with a positive log ofthe odds to base 10 score for a location on chromosome 7. The major remaining research challengesand the likely clinical benefits that should derive from genetic research are considered in relation toboth current knowledge and that anticipated to emerge from research over the next decade.

KEY WORDS: Autism; quantitative genetics; molecular genetics; functional genomics; clinical practice.

When Kanner (1943) first described the syndromeof autism, he suggested that it resulted from an inborndefect of presumably constitutional origin. Nevertheless,over the next 3 decades the possible role of genetic fac-tors tended to be dismissed. In part, this was because thezeitgeist at that time was one of expecting environmen-tal causes for all forms of psychopathology. This was theera of supposed “refrigerator” parents of autistic childrenand of “schizophrenogenic” mothers (see Rutter, 1999a).However, reviews by geneticists were equally dismissive(Hanson & Gottesman, 1976). Emphasis tended to beplaced on the lack of vertical transmission (i.e., the raritywith which children with autism had parents with autism),on the very low rate of autism in siblings (estimated at thattime at about 2%), and the lack of identified chromosomeanomalies associated with autism (Rutter, 1967).

1Social, Genetic, and Developmental Psychiatry Research Centre,Institute of Psychiatry, De Crespigny Park, Denmark Hill, LondonSE5 8AF, UK; e-mail: [email protected].

TWIN STUDIES

An awareness that the logic of these arguments wasfaulty led Susan Folstein and myself (Folstein & Rutter,1977a,b) to undertake the first small-scale (N = 21) twinstudy of autism. The reasoning on genetic influences wasfalse because follow-up studies had shown that it was veryrare for autistic people to develop love relationships, andvery rare for them to have children, and hence verticaltransmission would not be expected; relative to the rate ofautism in the general population (about 2 to 4 cases per10,000 as defined at that time), the rate of autism was veryhigh indeed; and the cytogenetic techniques available inthe 1960s were quite primitive, so that the failure to showanomalies was really noncontributory.

Two main findings from this first twin study werestriking. First, despite the small numbers, there was asignificant monozygotic–dizygotic (MZ-DZ) differencein concordance. The fact that the population base rateof autism was so low implied a strong underlying ge-netic liability. Second, concordance within MZ pairs in-cluded a range of cognitive and social deficits and notjust the seriously handicapping condition of autism itself.This implied that the genetic liability extended beyond

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“autism proper.” It also raised questions about the diag-nostic boundaries of autism and led to an appreciation ofthe need to consider the likelihood of a broader phenotypeof autism, or of lesser variants of the same condition.

During the 1970s and 1980s, there was a range ofmedical studies of autism demonstrating positive findings(Rutter, 1999b). A mixed bag of medical conditions weredescribed in association with autism—most notably atthat time congenital rubella (Chess, 1977; Chess, Korn &Fernandez, 1971). However, more recently, it became clearthat the association with autism was probably strongest fortuberose sclerosis (Smalley, 1998). In addition, there wasa similarly mixed bag of chromosomal anomalies foundin individuals with autism—with the fragile X anomalyprominent among them (Gillberg & Wahlström, 1985).These findings had two important implications. First, itcame to be accepted that systematic screening for medicalconditions and chromosomal anomalies was an essentialpart of the diagnostic appraisal of children referred forpossible autism. Second, it was apparent that autism mustbe assumed to be etiologically heterogeneous.

During the late 1980s and early 1990s, genetic re-search into autism advanced through further twin studies,genetic–family studies, and molecular cytogenetic inves-tigations. Both a Scandinavian twin study (Steffenburget al., 1989) and a further British twin study (Baileyet al.,1995) confirmed the great strength of genetic influenceson the underlying liability for autism. Because the latterstudy included several crucial methodological improve-ments over the earlier research, I concentrate on its find-ings. There were four key design features: First, there wastotal population screening for cases, with all clinics andspecial schools in the country contacted, and all twin regis-ters examined. Second, systematic standardized methodsof diagnosis using both parental interviews (Le Couteuret al., 1989) and observation of the child (Lordet al., 1989)were employed. Third, there was systematic screening formedical conditions and chromosomal abnormalities in or-der to focus on the study of genetic factors in idiopathicautism. Fourth, blood groups were used to test for zygos-ity. That was important because the marked behavioraldifferences associated with autism sometimes led parentsand professionals to infer that the twins were fraternal,whereas in fact they were MZ.

Four main findings were crucial (see Figs. 1 and 2).First, the huge disparity in concordance rates for autismbetween MZ (n = 25) and DZ (n = 20) pairs (60% vs.5%) confirmed the earlier findings on the strength of thegenetic influence. Quantitative analyses indicated a her-itability in excess of 90%. Second, the exceedingly lowrate of concordance in DZ pairs compared with that inMZ pairs pointed to the likelihood of epistatic effects in-

Fig. 1. Pairwise concordance for autism, social and cognitivedisorder (based on data from Baileyet al., 1995).

Fig. 2. Concordance for broader phenotype in MZ andDZ pairs discordant for autism (based on data fromLe Couteuret al., 1996).

volving synergistic interaction among several genes. Thepattern was not compatible with a single-gene Mendeliandisorder. Third, the finding that the genetic liability ex-tended to include a broader phenotype was confirmed.Some 90% of monozygotic pairs were concordant for mix-tures of social and cognitive deficits qualitatively similarto those found in traditional autism, but milder in degree(see Fig. 1). This applied, however, to only about 1 in10 DZ pairs. Focusing on the 10 MZ and 20 DZ pairsdiscordant for autism or pervasive developmental disor-ders (Fig. 2), it was shown that there was a similar con-trast in concordance for this broader phenotype, the dif-ference being statistically significant (Baileyet al., 1995).A follow-up of the Folstein and Rutter twin sample alsoshowed that this broader phenotype was associated withimportant deficits in social functioning that continued intoadult life (Le Couteuret al., 1996). Fourth, an examinationof 16 MZ pairs concordant for autism or atypical autismshowed that there was enormous clinical heterogeneityeven when pairs shared exactly the same genes. Surpris-ingly, individuals within MZ pairs were no more alike inIQ or symptomatology than were pairs of individuals se-lected at random from different twin pairs (Le Couteuret al., 1996).

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Genetic Studies of Autism 5

Fig. 3. Rates of disorder in siblings (based on datafrom Boltonet al., 1994).

FAMILY STUDIES

The second line of genetic enquiry was provided byfamily studies. These were important to determine the rateof autism in sibs and in parents, to check family patterns oftransmission in case there were Mendelian variants (thiscannot be assessed from twin studies), and to better de-lineate the breadth and pattern of the possible broaderphenotype.

The Maudsley Hospital family study used measure-ment methods directly comparable with those in the Britishtwin study, and similarly excluded families in which theautism was associated with some known medical condi-tion that was likely to be causal (Fig. 3; Boltonet al.,1994). The families of 99 individuals with autism werecompared systematically with the 36 families of individu-als with Down syndrome, using exactly the same methodsof measurement. There was direct assessment of all first-degree relatives and systematic standardized reports onmore distant relatives. The rate of autism in the siblings ofautistic individuals was found to be 3%, with 6% showingsome form of pervasive developmental disorder (PDD).No cases of autism or PDD were found in the siblings ofindividuals with Down syndrome. As in the twin study, abroader phenotype of autism, comprising mixed patternsof cognitive and social deficits and repetitive stereotypedinterest patterns, were even more frequent. Dependingon how stringent a definition was used, the comparativerates of the broader phenotype, as compared with Downsyndrome families, were about 12% versus 2% or 20%versus 3%.

The relative increase in risk in siblings was some-where between 30-fold and 100-fold, depending on theassumptions made about the base rate in the general pop-ulation. The increase in risk in MZ co-twins was 10 timesthat. The falloff in rate from MZ to DZ twins, togetherwith that from first-degree to second-degree relatives, was

used to estimate the number of genes that likely were tobe involved (Pickleset al., 1995). The findings effectivelyruled out the possibility of just one gene, and suggestedthat three or four genes were most probable, but any num-ber between 2 and 10 genes was a possibility (dependingon the relative strength of effect of any one of these).

The key conclusions from the twin and family stud-ies up to that point was that the heritability of an under-lying liability to autism was above 90%, that the liabilityextended well beyond the traditional diagnosis, and thatseveral interacting genes were likely to be involved. So farso good, but a range of crucial questions remained. Theseincluded queries on the role of medical conditions andchromosomal anomalies, the clinical indices of geneticheterogeneity, the defining features of the broader pheno-type, the relationship between the broader phenotype andtraditional autism, and the presence and characteristics ofphenocopies.

FRAGILE X ANOMALY

The early reports on the fragile X anomaly had ledto claims that this was a very common cause of autism(Gillberg & Wahlstrom, 1985). Subsequent studies usingthe original cell culture methods showed that, to the con-trary, fragile X anomalies were present in less than 5%of individuals with autism (Baileyet al., 1993; Dykens &Volkmar, 1997). The development of DNA techniques foridentification of the fragile X confirmed the infrequencyof fragile X in autism and, most especially, indicated thatthere were no cases of fragile X in individuals with 1–3%of fragile sites on the X chromosome—a proportion thathad been used for positive diagnoses in the early studies(Gurling, Bolton, Vincent, Melmer, & Rutter, 1997).

We need to pause, therefore, to consider what theflaws were in the original fragile X claims. Three featureswere probably most important: (1) a reliance on dubiouscell culture findings giving rise to only 1–3% of fragilesites; (2) a lack of care in clinical diagnosis; and (3) thefallacious assumption that positive findings from smallsamples are more likely to be valid (see Pocock, 1983).

CLINICAL INDICES OF GENETICHETEROGENEITY

It might be expected that etiological heterogeneitywould be associated with differences in clinical phenom-ena. It is possible that that will prove to be the case but,up to now, the indications are weak. The family studyfindings had shown that the more severe the autism, the

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greater the familial loading tended to be, as indexed by ei-ther symptomatology or verbal IQ, but this seemed to be agraded phenomenon rather than a categorical distinction.Some data on families (August, Stewart, & Tsai, 1981) hadsuggested that autism that was accompanied by profoundmental retardation might be somewhat different from therest of autism in which the nonverbal IQs were above 50.Accordingly, the Maudsley Hospital group undertook afurther family study to determine whether this might bethe case (Starret al., 1999; Pickleset al., in press). Thefindings were largely negative. The rate of autism and ofthe broader phenotype in the relatives was not significantlydifferent from the rates in the first family study. The onlypossible lead was the uncertain indication that cognitiveproblems in the relatives might be more common when theautism was associated with profound retardation. What didemerge, however, from the combination of the two studieswas the finding that the linear association between sever-ity of autism and familial loading seemed to apply onlyto cases of autism in which there was some useful speech(Pickleset al., in press). The implication is that, whenautism is associated with a very severe lack of languageskills, it might be genetically different in some way.

PHENOCOPIES

Over the past 10 years, evidence has accumulated,however, on the existence of what seemed to be pheno-copies—meaning clinical pictures that look like autism butthat are not due to the same genetic liability. Thus, atypicalsyndromes of autism have been found to be associated withcongenital blindness (Brown, Hobson, & Lee, 1997), withprofound institutional privation (Rutter, Andersen-Wood,et al., 1999), and with a mixed bag of medical conditions orwith profound mental retardation (Rutter, Bailey, Bolton,& Le Couteur, 1994). The evidence to date does not showdecisively that these syndromes do not involve any of thesame genetic liability but that is the implication of thefindings.

BROADER PHENOTYPE

During the past 20 years, there has been a grow-ing number of family studies of one kind or another thathave sought to delineate more precisely the nature ofthe broader phenotype of autism, together with identifi-cation of its boundaries. The Johns Hopkins study, ini-tially planned in collaboration with the Maudsley Hospitalstudy, was particularly important because of its evidenceon the probable importance of pragmatic language prob-

lems (Landa, Wzorek, Piven, Folstein, & Isaacs, 1991;Landaet al., 1992), of social abnormalities (Pivenet al.,1990, 1991), and of unusual personality features (Pivenet al., 1994). The early findings had particularly empha-sized the role of language delay but, although this doesseem to be part of the overall picture in some cases, thelater findings have suggested the probably greater im-portance of social deficits (Bailey, Palferman, Heavey, &Le Couteur, 1998; Folstein & Piven, 1991; Piven, Palmer,Jacobi, Childress, & Arndt, 1997; Rutteret al., 1997.)

As the evidence accumulated from a range of stud-ies of varying quality, more and more clinical features,including affective disorder and social anxiety (DeLong& Nohria, 1994; Smalley, McCracken, & Tanguay, 1995),came to be added to possible variations of the broaderphenotype. Clearly, there was a danger that it would be-come unhelpfully overinclusive and it was important tohave a means of ruling out, as well as ruling in, possi-bilities. In that connection, two largely negative findings(with respect to cognitive impairment and to depression)warrant mention. First, Fombonne, Bolton, Prior, Jordan,& Rutter’s (1997) detailed analysis of cognitive patternsin relatives in the Maudsley Hospital family study showedthat neither low IQ nor specific problems in reading orspelling showed an increased loading in the families ofindividuals with autism if these problems were not ac-companied by other manifestations of the broader phe-notype. Somewhat contrary to earlier impressions, it nowseems that such specific cognitive deficits, when they oc-cur in isolation, are not indicators of a genetic liability toautism. On the other hand, language impairments do con-stitute an important part of the broader phenotype; it is justthat they do not ordinarily appear to be related to autism ifthey occur without social deficits or circumscribed inter-est patterns. The same findings also showed the apparentlysurprising finding that the relatives tended to show a cog-nitive pattern with verbal skills that were superior to visualor spatial skills—namely, the opposite of what is ordinarilyfound in autism. Piven and Palmer (1997) found the same.

As in the Johns Hopkins study (Pivenet al., 1994),the Maudsley Hospital study showed an increase in therate of unusual personality traits in the relatives of autisticindividuals (Murphyet al., 1999). The traits of shynessand aloofness were especially frequent in those with othermanifestations of the broader phenotype and the traits ofanxiety and oversensitivity were especially frequent inrelatives who also had anxiety or depressive disorders.The rates of clinically significant affective disorder werealso increased in the relatives of individuals with autism(Bolton, Pickles, Murphy, & Rutter, 1998).

The finding that a phenomenon is increased in rela-tives does not, in itself, necessarily mean that it reflects a

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genetic liability. It is important to go on to test alternativepossibilities. This could be done, indirectly, in the familystudies by determining whether depression was associ-ated at the individual level with the broader phenotype ofcognitive and social deficits and similarly whether it wasassociated at the family level. The findings were clear-cutin indicating that it was not at either level. Depression wasassociated with depression in other family members butnot with the broader phenotype. At an individual level, too,it overlapped with other manifestations of affective disor-der but not with cognitive or social deficits. Also, unlikethe broader phenotype, the familial loading for affectivedisorder was not associated with the severity of autism.The cause of the increased rate of depression in the fami-lies of individuals with autism remains unclear but it doesnot seem to reflect a genetic liability to autism.

Putting together the findings on the broader pheno-type, it can be concluded that there is good evidence fromboth twin and family studies that the genetic liability in-cludes patterns of social and cognitive deficits accompa-nied by circumscribed interest patterns that are very sim-ilar to autism in quality but much milder. However, thereseem to be two crucial differences between the broaderphenotype and autism as traditionally discussed. Unlikeautism, the broader phenotype is not associated with men-tal retardation and it is not associated with epilepsy. Asyet, we do not know why that is so. Questions arise as towhether the broader phenotype represents a lesser “dose”of genetic liability, a different pattern of susceptibilitygenes, or some kind of “two-hit” mechanism, in whichsome additional risk factor is required in order to take in-dividuals over the threshold from the broader phenotypeto a more seriously handicapping disorder.

MOLECULAR GENETICS

During the 1990s, it became evident that use of mole-cular genetic strategies was indicated and that the technol-ogy had reached a point at which when the enterprise wasfeasible. In particular, the development of robotic tech-niques and the availability of a very large number of poly-morphic microsatellite genetic markers had made a to-tal scan of the genome a practical possibility (Maestrini,Marlow, Weeks, & Monaco, 1998). In planning a molec-ular genetic study, there were three features that madeautism a very good disorder for this approach and therewere three features that presented problems. The pluseslay in the very consistent evidence of a strong geneticliability, with a heritability for the underlying liability toautism above 90%, the evidence of a relatively small num-ber (probably less than 10) of susceptibility genes, and the

availability of good, well-standardized diagnostic mea-sures of proven reliability. The disadvantages lay in theabsence of good candidate genes, the lack of evidence onthe mode of genetic transmission, and considerable un-certainty on the boundaries of the phenotype. This meantthat linkage studies of large families were inappropriate,the lack of candidate genes meant that there were poorleads for any association study and hence the choice of anaffected sib-pair design was the obvious way to go.

It was possible to use well-standardized diagnosticmeasures to focus on a well-validated narrow diagnos-tic concept. It was appropriate, and possible, to excludeindividuals with profound retardation, to rule out casesthat might be due to medical causes, and, in addition, inview of the evidence on phenocopies, it seemed sensible toexclude individuals who had experienced unusually pro-found psychological privation. Also, systematic screeningfor multiplex families (meaning families with at least twoaffected members) was essential.

The likelihood of genetic heterogeneity, together withthe fact that the search needed to be for multiple suscep-tibility genes, meant that a large sample of sib pairs wasessential. Accordingly, an international consortium wasestablished, standard methods were set up to check onreliability, and a total genome scan was undertaken byMonaco and colleagues at the Wellcome Trust Centre forHuman Genetics. The findings produced a positive log ofthe odds to base 10 (LOD) score for a location on chro-mosome 7, together with more weakly positive findingsfor locations on five other chromosomes (InternationalMolecular Genetic Study of Autism Consortium, 1998).The LOD score is a statistical term that quantifies the like-lihood that two loci are linked or unlinked (Burmeister,1999), in this case a linkage between the location on chro-mosome 7 and one of the postulated loci for susceptibilitygenes for autism. A score of+3 or more is commonlyaccepted as showing linkage; in the study, the score foundfor the UK sample exceeded that cutoff. This finding con-stituted the first crucial step in the search for susceptibilitygenes for autism—meaning genes that are causally impli-cated in the liability to autism but which do not, on theirown, cause it directly. They provided the basis for a pos-sible breakthrough but it is important to recognize that itwas the beginning of the beginning, not the end of thebeginning, and certainly not the end of the search.

The history of psychiatric genetics is full of earlyclaims for positive findings that subsequently could notbe replicated and have had to be withdrawn, or at leastvery substantially modified (Rutter, 1994; Rutter, Silberg,O’Connor, & Simonoff, 1999a,b). Several further imme-diate steps needed to be taken. To begin, the InternationalConsortium increased the size of the affected-relatives

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sample to determine whether the LOD score holds up;it does. Even more crucially, as is the rule throughout sci-ence, replication in independent samples is mandatory. Nofinding is valid until it has been confirmed by other investi-gators. Discussions with other research groups throughoutthe world who have comparable sib-pair samples has ledto informal reports that they have similar, albeit weaker,positive findings in much the same position on chromo-some 7 (see also Philippeet al., 1999). What is needednow is some form of meta-analysis across the differentstudies and that is being planned.

One of the limitations of linkage studies (examiningco-inheritance, that is, inheritance within families in whichthere is linkage between the gene locus being studied andthe condition being investigated) is that a positive findingcovers a large area on the chromosome. Association stud-ies (based on the quite different strategy of using linkagedisequilibrium to search for differences between cases andcontrols in allelic patterns) can help to narrow this, and,in any case, it is always desirable to check whether a find-ing holds up using different strategies. The transmissiondisequilibrium test (TDT; Spielman & Ewens, 1996) con-stitutes the best method because it controls for stratifica-tion biases and because it tests for both association andlinkage (Malhotra & Goldman, 1999). The stratificationbias arises because cases and controls may differ in theirallelic patterns because they differ in their ethnic originsrather than for any reason to do with the disorder beingstudied. In that connection, it is important that the crucialethnic variations may be quite subtle, such as the differ-ence between having a Finnish rather than Swedish back-ground. The TDT has the advantage of requiring DNAsamples from only the affected child and both parents.Accordingly, it can and should be undertaken with single-ton samples as well as multiplex family samples. That isunder way in the laboratories of several of the researchgroups in the international consortium. In addition, it isdesirable, too, to make use of quantitative trait loci (QTL)approaches predicated on the expectation that susceptibil-ity genes may have effects on gradations in a continuouslydistributed phenotype, and not just on the extreme disor-der (Allison, 1997; Fulker & Cherny, 1996; Kruglyak &Lander, 1995).

Genomic clone contigs for chromosome 7q will needto be identified from genome maps or library screening,and then sequenced. These are cloned short sequencesof human DNA that have been inserted into some otherorganism. Then, computer analyses can be used to re-assemble the shorter sequences into longer ones (Watson,Gilman, Witkowski, & Zoller, 1992). Analyses of can-didate genes can focus on those at the already identifiedpeak of the linkage disequilibrium curve (Merrimanet al.,

1997, 1998) from the TDT. Genes expressed in the brain(i.e., affecting brain structure and/or function) can be sys-tematically tested for autism susceptibility variants, withputative variants tested in patients and controls.

Identification of a susceptibility gene on chromo-some 7 will, of course, only deal with a small part ofthe genetic liability and it will be necessary to go throughsimilar search processes, using larger samples, to identifyother susceptibility genes. However, the power to detectthem will have been increased by the identification of thegene on chromosome 7.

Association strategies have the advantage over link-age strategies of being better able to detect very smallgenetic effects (Risch & Merikangas, 1996). Up to now,however, they have relied on the availability of candidategenes. These have been singularly lacking in relation toautism. Nevertheless, some groups have attempted thisapproach, but the findings so far (with the possible excep-tion of the chromosome 15 finding—Cooket al., 1998;but see Maestriniet al., 1999) have been contradictoryand inconclusive (Cooket al., 1997; Klauck, Poustka,Benner, Lesch, & Poustka, 1997). The development ofthe technique of DNA pooling (i.e., combining DNA sam-ples across cases and similarly across controls) providesa possible way forward (Barcelloset al., 1997; Danielset al., 1998). It should be possible to use this techniquein a way that controls for stratification biases (meaningthat cases and controls are genetically different for rea-sons that have nothing to do with autism). The use ofparents as the control strategy, as in the TDT, overcomesthe problem. Accordingly, at least in theory, it should bepossible to undertake genome scans, using DNA pool-ing and an association strategy. This has yet to be shownto be a successful strategy and there are two main issues tobe dealt with. First, the number of markers required willbe very much greater than in linkage studies because theassociation strategies can produce positive findings onlyin relation to a susceptibility gene that is very close to themarkers used or is the trait marker itself. Second, thereare statistical problems in determining the significance ofcase-control differences when a very large number of genemarkers have to be tested. Nevertheless, this does consti-tute one additional possible way forward.

In addition, there needs to be a follow-through onfindings that apply to specific genetic disorders associatedwith autism. Tuberous sclerosis constitutes one possiblelead because of the evidence that a significant minority(less than 5%) of autistic individuals have tuberous scle-rosis and because the rate of autism has been shown tobe much increased in individuals with tuberous sclero-sis (Smalley, 1998). Chromosome 15 anomalies have alsoprovided a lead that needs to be followed (Cooket al.,

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1997; Schroeret al., 1998). It is notable that the associa-tion between autism and an intrachromosomal duplicationof 15q11-q13 seems to depend on maternal transmission.The possibility of genomic imprinting needs to be con-sidered. The precise mechanism involved in imprintingremains uncertain but the term means that the expression(or effect) of a gene is influenced by whether it is inheritedfrom the father or the mother. It seems that, in some way,the gene is marked (imprinted) in the process of trans-mission from parent to offspring. Several such genes havebeen identified in mice and humans (Barlow, 1995) andone is known to cause both Angelman and Prader-Willisyndromes (both are neuropsychiatric conditions) accord-ing to whether the gene comes from the mother or thefather (see Rutteret al., 1999a).

It may be anticipated confidently that, over the nextfew years, these various research approaches will be suc-cessful in identifying several susceptibility genes forautism. However, in itself, that will not have clinical bene-fits. Much more needs to be done (Wahlsten, 1999). Thus,it is necessary to go on to clone the susceptibility genes, todetermine the gene effects on proteins, and to delineate theroute from these gene effects to the autism phenotype. Theapplication of this approach to traditional autism clearlyconstitutes the first application to be undertaken. Never-theless, it will be necessary to go on to validate the broaderphenotype and to apply the range of molecular geneticstrategies to that phenotype. It will be important to seekto develop dimensional phenotype measures and, havingdone so, to use QTL approaches with markedly discordantsib pairs. At present, we do not know whether there is adimensional equivalent of autism but that remains a realpossibility that needs to be explored.

NEED FOR QUANTITATIVE GENETIC STUDIES

It is sometimes thought that the day of quantitativegenetics is over, but it is not. Thus, in relation to autism,there is a need for twin and family studies of broader phe-notypes. At the moment, we know something about theoccurrence of such phenotypes in the relatives of indi-viduals with autism but there are no adequate studies inwhich the starting point is probands with the broader phe-notype. There is also more scope for studies of within-and across-MZ pair variations in order to explore possibleclinical indicators of genetic heterogeneity. For example,this needs to be done with respect to both epilepsy andlanguage level. The cause of the marked male preponder-ance in cases of autism is quite unknown and leads mightbe provided by male/female comparisons within multi-plex families. Also, family studies of head circumference,

serotonin level, and other correlates of autism might beinformative.

One obvious priority concerns research to under-stand the phenomenon of the broader phenotype. Up tonow, it has largely been conceptualized and measured asa lesser variant of autism. Its assessment needs to rely ona combination of social deficits, communicative deficits,and repetitive stereotyped interests as observed and as re-ported by the individuals themselves and by others. Asalways, multiple methods of assessment, using differentdata sources, are necessary. Some guidance may be pro-vided by the age of first manifestation. In addition, there isconsiderable potential in using the pattern of social cog-nitive abnormalities as a validating criterion. There area variety of indications in the literature that this mightbe fruitful (see, e.g., Hughes, Leboyer, & Bouvard, 1997;Hughes, Plumet, & Leboyer, 1999) but, to apply the leadsin a systematic way, such abnormalities would need to bedimensionalized and quantified, and then related to othermeasures of social functioning. Probably the greatest po-tential lies in some combination of theory of mind skills astested in naturalistic ways (see, e.g., Baron-Cohen, 1995;Happe, 1994; Heavey, Phillips, Baron-Cohen, & Rutter, inpress) and pragmatic qualities in conversational language(Landaet al., 1991, 1992), but central coherence features(Frith & Happe, 1994) and aspects of executive plan-ning (Hughes,et al., 1999; Ozonoff, Rogers, Farnham,& Pennington, 1993; Piven & Palmer, 1997) also need tobe considered. However, it is likely that executive plan-ning deficits may well prove to lack diagnostic specificity(Griffith, Pennington, Wehner, & Rogers, 1999).

Two key comparisons are required. First, there is aneed to determine the difference in frequency of the lesservariant between relatives of probands with autism and rel-atives of probands with schizophrenia or some other con-dition that is genetically distinct from autism but whichinvolves a familial loading for social problems. This needsto be followed by an analysis to determine the differencesin the particular pattern of the phenotype between thosewith abnormalities in the two groups. The point is thatthere are many different causes of social communicativeand behavioral problems in human beings and it is cru-cial to be able to determine what is distinctively differentabout those that index autism.

How can we get to that point? The start, I suggest, isa focus on abnormalities found in individuals with autismwho have normal levels of nonverbal intelligence. The firsttask, then, is to determine the confluence among the variedmeasures; that is, the extent to which, say, theory of minddeficits is associated with abnormalities in social reci-procity and pragmatic language impairment. This needs tobe followed by the validation of group differentiation and

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to go on to the establishment of means of diagnosis at anindividual level. Finally, the diagnosis of the broader phe-notype must be related to studies of brain functioning (asby functional imaging) and to genetics (using moleculartechniques). As already noted, there are important dif-ferences between the broader phenotype and traditionalautism, and it is necessary to undertake research to deter-mine whether this is a consequence of a different genetic“dose,” different gene patterns, or the operation of somenongenetic factor, as yet to be identified.

In the past, psychiatric geneticists have tended tothink of genetic effects as if they operated at a syndromeor diagnostic level. Of course, that may be how they work.On the other hand, it is crucial to consider the possibilitythat the genetic effects operate on components of autism,rather than the syndrome as such. For example, there areindications that that could be the case in relation to read-ing difficulties (Fisheret al., 1999; Gayán et al., 1999;Grigorenkoet al., 1997). This means that genetic stud-ies must be undertaken in relation to both possibilities.That would require the separation and dimensionalizationof different components (not just in relation to symptompatterns but also in terms of cognitive level and unusualcircumscribed cognitive talents). In addition, it will beimportant to consider the possibility that the susceptibil-ity genes for autism may include some that are involved inthe liability to developmental language disorders, with thegenetic-effects ones that are not diagnosis-specific. In thatconnection, it is interesting that the locus found for an un-usual form of familial speech/language disorder (Fisher,Vargha-Khadem, Watkins, Monaco, & Pembrey, 1998) issituated quite close to that on chromosome 7, which seemsto link with autism. Recent research has shown that the“theory of mind” deficits associated with autism are alsofound with some severe developmental disorders of re-ceptive language (Clegg, Hollis, & Rutter, 1999). Also, itwill be important to consider the possibility that the riskprocesses involve the absence of protective genes as wellas the presence of susceptibility genes.

FUNCTIONAL GENOMICS

In looking ahead into the Millennium, we need toconsider what is going to be required for the genetic find-ings in autism to be translated into clinically useful meansof prevention or treatment. Genetic evangelists tend to im-ply that this will automatically follow in a relatively shortperiod of time. It will not. There is a long journey to be un-dertaken (Fig. 4) to go from the identification of genes tothe development of effective new therapies (Chakravarti,1999). Also, it is evident that this journey will involve

Fig. 4. The long journey from genes to therapy.

bringing together quite diverse areas of science. As iswell recognized, susceptibility gene identification has be-come possible through advances in molecular genetics andthrough the information provided by sequencing the hu-man genome. The development of single nucleotide poly-morphisms and of microarray chips will further aid thisendeavor (Brown & Hartwell, 1998; Lander, 1999; Watson& Akil, 1999). The steps required to understand the func-tion of these genes are many and varied and it has to berecognized that there is not yet a well-established path forthis research process. On the one hand, there is the researchfocusing directly on the genes themselves with various an-imal models a crucial part of the process, but with bioin-formatics essential, too, in the linking up of informationacross species and across different research approaches.Transgenics, gene insertion, and gene “knockout” tech-niques have a crucial part to play in the identification ofgene function because they provide an experimental ap-proach to gene actions (Capecchi, 1994; Crabbe, Belknap,& Buck, 1994; Sibilia, & Wagner, 1996). However, thesemethods are likely to be difficult to apply in autism becauseof the problems of measuring the relevant phenotypic fea-tures in mice (Rutteret al., 1999a). Also, it will be cru-cial to use the new technologies of proteomics (the studyof protein properties) and transcriptomics (the variety oftechnologies for screening for messenger RNA content).All of this constitutes components of the broader multidis-ciplinary field of functional genomics, a field that is stillat quite an early stage of development.

Having found out the nature of gene functions, thenext step involves identification of the risk process bywhich the anomalies of gene function lead to the phe-notype of autism. This will require research to understandthe workings of the biological system (molecular cell bi-ology) but it will also involve the determination of howthe genetic risks interact with developmental processesor with environmental hazards of some kind (requiring

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molecular epidemiological research). If all of this is suc-cessful in its aims, it then should be possible to move on tothe further step of outlining the disease model. That willrequire integrative biological studies that are combinedwith experimental testing in order to determine whetherthe model is correct in its details as well as in its overallform. Of course, even the construction of a valid diseasemodel does not in itself provide clinically effective meth-ods of prevention or treatment. That requires yet furtherresearch steps, which there is not space to consider here.

CLINICAL BENEFITS OF GENETIC RESEARCH

Let me end, nevertheless, on a more positive noteby outlining the potential benefits that may be anticipatedfrom these research endeavors. The topic may be con-sidered under the broad question of how genetic findingsmight matter for families that contain an autistic individ-ual. There are seven main benefits, some of which havealready been obtained. First, the genetic findings have al-ready had an effect on the prevailing concepts of the na-ture of autism. We now focus on genetically influencedneurodevelopmental deficits rather than on maladaptivepatterns of upbringing. There are, of course, still querieson the nature of these deficits, and the possibility of inter-acting environmental risks has not been ruled out.

Second, the findings raise the need for the availabil-ity of genetic counseling. In such counseling, it is nec-essary to focus on the contrast between the rather lowlevel of absolute risk and the high level of relative risk ofautism in other family members. The queries in this con-nection mainly concern the risks for autism-related butless-handicapping disorders.

Third, there is the potential of molecular genetic find-ings to provide a better identification of the broader phe-notype. This will allow a focus on which developmentaldelays, cognitive features, and social deficits are part of anautism liability. However, the connections between autismand the broader phenotype may prove to be quite complexand difficult to determine.

Fourth, there is the potential of molecular geneticfindings for leads on biological research that will identifythe causal neural processes that underlie the developmentof autism. These will allow a focus on the specific neuro-biological effects of susceptibility genes and on the routesby which such effects predispose to autism. As I have in-dicated, the identification of causal processes could leadto effective means of prevention or intervention, but theresearch route is likely to prove long and arduous.

Fifth, there is the potential of molecular genetic find-ings for leads on possible protective factors. There needs

to be a focus on possible protective genes as much as onnongenetic influences. This focus might throw light onwhy autism is so much more frequent in males, as wellas on the mechanisms involved in the transition from thebroader phenotype to the handicapping disorder of autism.Sixth, there is the potential of molecular genetic findingsfor leads on effective drug treatments. This will involve afocus on specific pharmacological actions and, most espe-cially, on individual differences in response to medication.The extent to which this will lead to effective interventionswill depend to a considerable extent on what proves to bethe nature of the underlying neural processes and on howthey predispose to autism.

Finally, there is the potential of molecular geneticfindings in aiding the identification of environmental risks.This will require a focus on nature–nurture interplay andon the delineation of the role of environmental media-tion of risks. Autism is a complex multifactorial disor-der and the evidence suggests that the risks are likely toinvolve nongenetic, as well as genetic, factors, althoughthe latter are probably much the most powerful influence.At present, we know very little about these nongeneticfactors and it may be that the nongenetic vulnerabilitiescould be proven to reside in random developmental vari-ations (Goodman, 1991; Kurnit, Layton, & Matthysse,1987; Molenaar, Boomsma & Dolan, 1993) rather than ei-ther obstetric or postnatal influences (Boltonet al., 1997).Still, we need to understand what these factors are andhow they operate. It is possible, in that connection, thatdermatoglyphic patterns (Davis & Bracha, 1996) or mi-nor congenital anomalies (Meyers, Elias, & Arrabal, 1995)might provide some index of developmental perturbations.

CONCLUSION

The past 30 years has seen tremendous advancesin the understanding of the role of genetic influences inautism. We have come a long way from the views of theearly 1970s when even behavior geneticists doubted thatthere were any genetic effects to be investigated in autism.We now know that, despite that early skepticism, geneticinfluences are hugely important in the liability to autism,that they involve the operation of several interacting genes,and that the liability extends well beyond traditional con-cepts of a handicapping disorder usually accompanied bysome degree of mental retardation, and often with the de-velopment of epilepsy in adolescence. In concluding thispaper, I have tried to look ahead into the next 30 years.I think there is every reason to be optimistic about thelikelihood that the genetic research will lead to biologicalstudies that will, at last, delineate the underlying causal

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12 Rutter

neural processes and that their understanding will havesubstantial clinical benefits. For this research program tobe successful, it will need to combine clinical, epidemi-ological, and basic science strategies and it will dependon crucial advances in several of these fields. Only timewill tell whether my optimism on the likely success ofthis endeavor will prove to be justified. If it is successful,however, clinical practice with individuals suffering fromautism in its several varieties is likely to be transformed.

ACKNOWEDGMENTS

This paper was given as the Presidential Address atthe Ninth Biennial International Society for Research inChild and Adolescent Psychopathology Conference heldin Barcelona, Spain, July 16–20, 1999. The ideas and find-ings in this paper owe much to the many splendid collab-orators with whom it has been my good fortune to workin the field of the genetics of autism. I would like to ex-press particular appreciation of the contributions over theyears of Anthony Bailey, Patrick Bolton, Susan Folstein,Eric Fombonne, Ann Le Couteur, Catherine Lord, An-thony Monaco, and Andrew Pickles. To an even greaterextent, I am indebted to the numerous families who haveparticipated in our studies.

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Documents

Genetic Studies of Autism: From the 1970s into the Millennium